DETAILED ACTION
Claims 16-33 are pending in the instant application and being examined on the merit.
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 .
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because the x-axis values in Figs 4, 5, and 6A and B are not legible. The characters along the x-axis appear blurred such that the axis values cannot be read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
“claudin18” should read “claudin 18” (page 23, ¶[0096]); and
Throughout the specification, SEQ ID NO:13 is used to describe the light chain
CDR2 of the Claudin 18.2 binding entity and it is a skipped sequence in the sequence listing. The sequence listing and CRF were entered under ST26 where sequence identifiers corresponding to 3 amino acids or less are shown as skipped sequences. Applicant is required to amend the specification of all the sequence identifiers corresponding to a skipped sequence with the specific sequences. See pages 3, 4, and 18.
Appropriate correction is required.
The use of the term Tween®, CytoFlex® which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. All trademarks referenced herein should be identified as such with the appropriate notation:
Tween® (page 24, ¶[0097], ¶[0098]); and
CytoFlex® (page 25, ¶[0099], ¶[0101])
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 16-17 and 19-22 are objected to because of the following informalities:
Regarding instant claims 16-17 and 19-22, “4-1 BB” should read “4-1BB” for consistency with claim 32, drawings and the specification;
Regarding instant claim 20, there should be an “and” after the semicolon at the end of (7).
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 17 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding instant claim 17, SEQ ID NO:13 is a skipped sequence in the sequence listing and CRF. Page 18 of the specification recites sequence identifier SEQ ID NO:13 and the corresponding sequence as WAS. The sequence listing and CF was entered under ST26 where sequences that are 3 amino acids or less are listed as skipped sequences. Currently, the corresponding sequences for the light chain CDR2 are disclosed in the Table under “Description of Sequences” in the instant specification. Applicant is required to amend SEQ ID NO:13 of claim 17 with “WAS”.
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 16 and 18-33 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. This is a WRITTEN DESCRIPTION rejection.
Scope of the claims
Claims 16-33 are directed to a bispecific antibody that binds Claudin 18.2 and 4-1BB or a nucleic acid molecule encoding said bispecific antibody, wherein the bispecific antibody is claimed to comprise (i) a Claudin 18.2 binding entity comprising two pairs of identical immunoglobulin chains, wherein each pair of immunoglobulin chain has a light and heavy chain, the heavy chain comprising a heavy chain variable region (VH) comprising a VH-CDR1 or a variant thereof, a VH-CDR2 or a variant thereof, and a VH-CDR3 or a variant thereof as set forth in SEQ ID NO:1; and light chain comprising a light chain variable region (VL) comprising a VL-CDR1 or a variant thereof, a VL-CDR2 or a variant thereof, and a VL-CDR3 or a variant thereof as set forth in SEQ ID NO:2, and (ii) a 4-1BB binding entity connected to the C-terminus of the heavy chain of the Claudin 18.2 binding entity wherein the 4-1BB binding entity comprises a VH-CDR1 or a variant thereof, a VH-CDR2 or a variant thereof, and a VH-CDR3 or a variant thereof as set forth in SEQ ID NO:3 or SEQ ID NO:25, wherein the variant has a substitution, deletion or addition of 1, 2, or 3 amino acids as compared to the sequence from which it is derived. Claims 29-33 require that the bispecific antibody binds to Claudin 18.2 and 4-1BB to treat a tumor in a subject.
Summary of Disclosed Species in the Original Specification
The anti-Claudin 18.2 x 4-1BB bispecific antibodies (biAb) in the Applicant disclosure (See Examples 1-8 on pages 23-29) represent anti-Claudin 18.2 and anti-4-1BB bispecific antibodies that the Applicant was in possession of at the time of filing, wherein:
the heavy chain of the bispecific antibody comprises the amino acid sequence as set forth in SEQ ID NO:6, which contains the amino acid sequence SEQ ID NO:1 of the heavy chain variable region of the monoclonal antibody anti-Claudin 18.2 mAb against claudin18 isoform 2 (Claudin 18.2), and the amino acid sequence (SEQ ID NO:3) of the 4-1BB binding region of the single domain antibody against 4-1BB, wherein, the N-terminus of the 4-1BB heavy chain variable region is connected to the C-terminus of Fc through a flexible peptide (SEQ ID NO:5); and
the light chain of the bispecific antibody comprises the amino acid sequence as set forth in SEQ ID NO: 7, which contains the amino acid sequence SEQ ID NO:2 of the light chain variable region of the monoclonal antibody anti-Claudin 18.2 mAb against claudinl8 isoform 2, and the amino acid sequence SEQ ID NO:8 of human kappa light chain constant region (CL) at the C-terminus of the VL amino acid sequence.
However, the specification does not describe any other combination of variants of CDR sequences wherein the variant comprises a substitution, deletion or addition of amino acids as compared to the sequence from which it is derived from. The specification does not disclose a representative number of bispecific antibodies with the claimed binding characteristics. As described above, the disclosed bispecific antibody has a specific CDR structure that binds a particular Claudin 18.2 and 4-1BB; however, the specification does not disclose a correlation of structure with function by means of a representative number of Claudin 18.2 and 4-1BB binding entities that have the requisite claimed functional properties. Therefore, the specification does not provide for a structure-function correlation of bispecific antibodies representative of the full scope of the genus. Furthermore, it is clear that the specification does not describe bispecific antibodies with particular functional properties or combinations of different “variants” of CDRs. The specification does not describe a correlation of the structure of the Claudin 18.2- or 4-1BB-binding entities with the functional properties as claimed (e.g. variants with amino acid differences or percent identical variants) absent in the presence of the specifically disclosed CDRs in specific order that conveys the structure that correlates with the binding function as claimed. Given the variations to the CDRs and to any framework regions that affect binding do not have description for the broad scope of the claims, Applicant was not in possession of the invention as claimed.
State of the Prior Art
At the time of filing, antibody functionality was known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that mutation to CDRs is unpredictable and that each construct requires function testing (Sela-Culang et al, “The structural basis of antibody-antigen recognition”, 2013, Fron. Immuno., 4(302): 1-13; hereinafter Sela-Culang). Sela-Culang reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition (page 1, Abstract; page 3, “The Role of CDRs and their Definition” section). A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized (page 1, “The Motivations for, and Applications of, the Study of Ab-Ag Recognition” Section).
It is well established that changes in the amino acid sequence of the variable region of an antibody create new antibodies with highly unpredictable binding characteristics. See for example Chen et al (Chen et al, “Enhancement and destruction of antibody function by somatic mutation: unequal occurrence is controlled by V gene combinatorial associations”, 1995, The EMBO Journal, 14(12):2784-2794). Chen teaches that the substitution of a single amino acid can totally ablate antigen binding (Figure 1), however, the reference additionally teaches that the same substitution in closely related antibodies can have opposite effects. The authors compared the effects of identical substitution in related antibodies D16 and T15, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. Additionally, Rudikoff et al (Rudikoff et al, “Single amino acid substitution altering antigen-binding specificity”, 1982, PNAS 79:1979-1983) teach that such is necessary and conventional to define an antibody that specifically binds a cognate antigen.
Further, Herold (Herold et al, “Determinants of the assembly and function of antibody variable domains”, 2017, Nature Scientific Reports, 7(12276):1-17; hereinafter Herold) teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected, because antigen binding is affected by each CDR loop differently and changes thereto can, in principle, affect antigen binding affinity in an unpredictable way (page 14, paragraph 2). Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex ( page 14, paragraph 3). Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Rudikoff et al, “Single amino acid substitution altering antigen-binding specificity”, 1982, PNAS 79:1979-1983). Rudikoff et al teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
At the time of filing, Jiang 1 (Jiang et al, “Abstract 5644: Claudin 18.2 - 4-1BB bispecific antibody induced potent tumor inhibition through tumor-specific 4-1BB activation”, 2020, Cancer Res, 80:5644; hereinafter Jiang 1) teaches Claudin 18.2 (CLDN18.2) is believed to be an ideal tumor antigen for immunotherapy, and the development of a bispecific antibody targeting CLDN18.2 and 4-1BB (TJ-CD4B) showed stronger binding capability to CLDN18.2 when compared with benchmark CLDN18.2 monoclonal antibody (IMAB362). Additionally, Jiang 1 teaches that functional evaluation of TJ-CD4B indicated that the activation of 4-1BB signaling was solely dependent on CLDN18.2 expression on the cell, and TJ-CD4B showed superior 4-1BB activity than benchmark 4-1BB monoclonal antibody (urelumab) in the presence of cells expressing a wide range of CLDN18.2 levels (Introduction section).
Jiang 2 (Jiang et al, WO2021027850A1, Priority to 8/12/2019; hereinafter Jiang 2) anti-claudin 18.2 and anti-4-1BB bispecific antibodies, wherein the antibody format comprises structure shown in Fig. 1, e.g. anti-CLDN18.2 unit is located at the N-terminal side of the anti-4-1BB unit. Jiang 2 also discloses examples of VH/VL amino acid sequences comprising distinct CDR sequences that comprise the anti-CLDN18.2 binding unit (page 18, ¶[0067]-page 20, ¶[0070]; Table C), and VH/VL amino acid sequences comprising distinct CDR sequences that comprise the anti-4-1BB binding unit (page 16, ¶[0064]-page 18, ¶[0066]; Table A and B), wherein the bispecific antibody 1A10 was noted to display efficient activation of 4-1BB signaling in a CLDN18.2-binding-dependent manner (pages 13-14, ¶0051]). Furthermore, Jiang 2 discloses binding kinetics of the antibodies 41B01 and 41B02, wherein although both antibodies had high 4-1BB binding affinities, the differences in the VH/VL regions resulted in differences in KD values (page 44, ¶[0130], §5.3 Protein Kinetic for 4-1BB;Table 5).
The prior art, however, does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in an anti-Claudin 18.2 and anti-4-1BB bispecific antibody that would allow prediction of CDR residues that specifically bind to Claudin 18.2 and 4-1BB antigens. Thus, making changes to the CDR sequence of an antibody sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Conclusion
For all the foregoing reasons, in view of the substantial genus of variant bispecific antibodies that bind Claudin 18.2 and 4-1BB, the numerous factors impinging binding and function of the bispecific antibodies to the target and also having the specifically claimed function, and the lack of description of a representative number of bispecific antibodies that function as claimed, the bispecific antibody comprising Claudin 18.2 and 4-1BB binding entities is not described in the specification in such a way as to reasonably convey to one skilled in the art that the Applicant, at the time the application was filed, had possession of the claimed invention. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 6 CDRs in an antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claims 16 and 18-33 would need to recite the 6 CDRs in the antibody that bind antigens Claudin 18.2 and 4-1BB without variability in the sequences thereof.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
Claims 30 and 31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a tumor in a subject, the method comprising administering to a subject in need thereof an effective amount of the bispecific antibody that binds to Claudin 18.2 and 4-1BB comprising sequences of SEQ ID NOs:9-14 and SEQ ID NOs:15-17, respectively, does not reasonably provide enablement for a method of preventing a tumor in a subject, the method comprising administering to a subject in need thereof an effective amount of the bispecific antibody that binds to Claudin 18.2 and 4-1BB comprising sequences of SEQ ID NOs:9-14 and SEQ ID NOs:15-17, respectively. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. In In re Wands, 8 USPQ2d 1400 (Fed. Cir., 1988) eight factors included for determining enablement:
The breadth of the claims;
The nature of the invention;
The state of the prior art;
The level of one of ordinary skill;
The level of predictability in the art;
The amount of direction provided by the inventor;
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The following is an analysis of these factors in relationship to this application
Scope of the claimed genus and nature of the invention
Claims 30 and 31 are for a method for preventing and/or treating a tumor in a subject, the method comprising administering to a subject in need thereof an effective amount of the following:
The bispecific antibody that binds to Claudin 18.2 and 4-1BB comprising sequences of SEQ ID NOs:9-14 and SEQ ID NOs:15-17, respectively, or
An immunoconjugate comprising the bispecific antibody.
The instant specification does not provide a definition for the term “preventing.” Absent a definition in the specification, the term is given its broadest reasonable interpretation consistent with the specification as it would be understood by one of ordinary skill in the art, wherein the conventional meaning of “preventing” is to keep something from happening or stop something from occurring at all. Accordingly, the claimed method of preventing a tumor means a method comprising administering the recited bispecific antibody to a subject in whom no tumor is present, in an amount effective to keep a tumor from arising at all such that the tumor does not develop in the subject.
State of the Relevant Art; level of one of ordinary skill; and level of predictability in the art
Cancer has a wide variety of causes, from environmental and/or developmental exposure to ionizing radiation and/or chemical exposure in addition to some types viral and bacterial exposure (Lichtman, “A Bacterial Cause of Cancer: An Historical Essay”, 2017, The Oncologist, 22(5): 542-548). Even though cancer is featured by dysregulated cell proliferation, its pathogenesis is extremely complex and related to many mechanisms. In general, the hallmarks of cancer consist of ten biological capabilities during the development of cancers, namely sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, tumor-promoting inflammation, genome instability and mutation, evading immune destruction and reprogramming energy metabolism (Hanahan et al, “Hallmarks of Cancer: The Next Generation”, 2011, Cell, 144(5): 646-674, Figures 1 and 3). More than 100 types of cancer have been identified which are typically termed for the organs or tissues where they occur. Hanahan taught over the past decade, tumors have increasingly been recognized as organs whose complexity approaches and may even exceed that of normal healthy tissues (page 661, right column second to last paragraph). Hanahan taught many human tumors are histopathologically diverse, containing regions demarcated by various degrees of differentiation, proliferation, vascularity, inflammation, and/or invasiveness (page 662, left column, first paragraph).
Clinical trials aimed at proving preventative cancer activity attributable to a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossible long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a selected few malignancies for treatments such as tamoxifen and finasteride (Lee et al, “Molecular targets of phytochemicals for cancer prevention”, 2011, Nature Reviews Cancer, 11: 211-218; page 211, left column last paragraph). Lee further taught although many reports have suggested benefits and targets of phytochemicals, these reports mainly rely on cell and animal models (page 216, right column last paragraph). Lee taught that in order to apply phytochemicals as personalized cancer preventive agents, the effects of phytochemicals in humans will need to be assessed (page 216, right column last paragraph).
The state of the art at the time of filing is described in the written description rejection above. Furthermore, Jiang 1 teaches that CLDN18.2 is a gastric-specific membrane protein wherein in the healthy tissue, CLDN18.2 expression is restricted to the gastric mucosa as a component of tight junction. However, Jiang 1 discloses that it is ectopically expressed at significant levels in a variety of primary lesion and metastases of epithelial tumor entities, including gastric, pancreatic, esophageal and lung adenocarcinoma cells. Taken together, Jiang 1 teaches that CLDN18.2 is believed to be an ideal tumor antigen for immunotherapy (Introduction section). However, there is no guidance in the instant disclosure or the art regarding prevention of cancer comprising administering a bispecific antibody that binds to Claudin 18.2 and 4-1BB comprising sequences of SEQ ID NOs:9-14 and SEQ ID NOs:15-17, respectively.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor; existence of working examples; and quantity of experimentation needed to make and use the invention based on the content of the disclosure
The specification discloses an anti-Claudin 18.2 x 4-1BB bispecific antibody as disclosed above in the written description rejection. Regarding methods of treating cancer, the instant specification uses human MC38-hClaudin 18.2 cells and h-4-1BB transgenic C57BL/6 mouse model to determine the anti-tumor effects of the bispecific antibody, wherein the MC38-hClaudin 18.2 cells were inoculated into female 8-week old h-4-1BB transgenic mice and divided into 4 groups according to tumor volume, wherein the mice were injected with different doses of the bispecific antibody. As shown in Fig. 7, compared to the control (PBS) group, CLDN18.2 monoclonal antibody and the combined administration of anti-CLDN18.2 monoclonal antibody with an anti-4-1BB single domain antibody had minimal inhibitory effect on tumor growth wherein the Claudin 18.2x4-1BB biAb at the same molar dose significantly inhibited tumor growth (see page 27-29, Examples 7 and 8; Tables 2 and 3; Figs. 7 and 8). However, the mice already had cancer before treatment with the bispecific antibody. Furthermore, there are no cancer prevention studies in the instant specification.
Conclusion
The applicant does not have enablement for the complete scope of the method for preventing a tumor in a subject, the method comprising administering to a subject in need thereof an effective amount of the bispecific antibody that binds Claudin 18.2 and 4-1BB that binds to Claudin 18.2 and 4-1BB comprising sequences of SEQ ID NOs:9-14 and SEQ ID NOs:15-17, respectively.
Claims 16 and 18-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a bispecific antibody which comprises a Claudin 18.2 binding entity and a 4-1BB binding entity wherein the Claudin 18.2 binding entity comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in SEQ ID NO:1; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in SEQ ID NO:2, does not reasonably provide enablement for a bispecific antibody wherein the Claudin 18.2 binding entity comprises only the heavy chain (VH) or only the light chain (VL). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed.
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
Claim 16 encompasses a bispecific antibody that binds Claudin 18.2 and 4-1BB wherein the Claudin 18.2 binding entity comprises two pairs of identical immunoglobulin chains, each pair comprising a light chain and a heavy chain comprising a VL and VH, respectively, where the Claudin 18.2 binding entity comprises only the VH or only the light chain. The instant claims 16, 18, and 22 required that the binding entity of Claudin 18.2 only expresses the heavy chain or only expresses the light chain. Claims 17, 19-21, and 23-33 are dependent on claim 16.
It is well documented in the prior art that during B-cell development, the VH genes are rearranged to generate a functional VH polypeptide that pairs with a surrogate light chain comprising VpreB and l5 light chain to form a pre-B receptor (Janeway, Immuno Biology The immune system in Health and Disease, 4 edition, 1999, pages 195-209, of record; figure 6.2 and 6.9 in particular). The association of the VH polypeptide with the surrogate light chain stabilizes the VH polypeptide, which is required for expression on the cell surface. B cells lacking the expression of a surrogate light chain do not produce functional VH polypeptides (Janeway et al., page 205, paragraphs 1 and 2 in particular). Following stable VH expression, the VL genes are rearranged in the developing B cell to generate a functional VL polypeptide, which then replaces the surrogate light chain to form a functional antibody comprising a VH-VL (Janeway et al., figure 6.2 in particular). The teachings of Janeway shows that both the VH and VL polypeptides need to be expressed in the same cell in order to produce stable VH and VL polypeptides to form an antibody.
Furthermore, Wijesuriya et al. (Protein Expression and Purification, 2018, 149:75-83, of record) showed that the expression level of the VH polypeptide is dependent on the expression of the VL in the same cell (see 3.5 Antibody engineering to improve mAB B-c expression in particular). Wijesuriya et al. showed that laboratories have altered the expression levels and sequences of the VL to improve the expression of the VH and overall antibody production (abstract; see discussion in particular). These data shows that similar to antibody production in B cells, expression of an engineered VH polypeptide requires the expression of a VL polypeptide.
Additionally, the prior art has taught single variable domains from species with VH and VL antibody pairing is distinct from other species with single domain only antibodies. (Holliger et al. “Engineered antibody fragments and the rise of single domains”, Nature Biotechnology, 2005, 23:1126-1136). Holliger taught that despite early excitement concerning the functional activity of single variable heavy domain antibodies, these antibody fragments rarely retained the affinity of the parent antibody and were also poorly soluble and often prone to aggregation (page 1127, left to right column bridging paragraph). Holliger taught while high affinity single variable like domain antibodies are present in camelid, as VHH, and shark, as V-NAR, domains, these single domain antibodies are structurally different, wherein each display long surface loops, often larger than for conventional murine and human antibodies, and are able to penetrate cavities in target antigens, such as enzyme active sites (for example, lysozyme) and canyons in viral and infectious disease biomarkers (page 1127, left to right column bridging paragraph). Holliger taught the structural changes are shown in Fig. 2, wherein superimposition of a human VH domain (Fig. 2b) and a single domain V-NAR(Fig. 2c) has a vastly different CDR3 that does not overlap structurally (Fig. 2d). Holliger taught unlike mouse VH domains, camelid VhH and shark V-NAR domains are in general soluble and can be produced as stable in vitro targeting reagents (page 1127, right column, second paragraph). Holliger did not describe single domain VL antibodies as successful.
Even the examples of the instant application disclosed co-express the VH and VL sequences for the Claudin 18.2 binding entity in the bispecific antibodies (Fig. 1; Examples 1-8). The instant specification has not shown that the Claudin 18.2 binding entity express a VH alone or a VL alone in the bispecific antibody to generate a functional bispecific antibody.
In light of the state of the art and these references, the specification fails to teach how to make and use the broadly claimed invention without undue experimentation. Thus, claims 16 and 18-33 are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
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 16-33 are rejected under 35 U.S.C. 103 as being obvious over Du (Du et al, US20210403552A1, Priority to October 22, 2018, IDS entered on 5/10/2024; hereinafter Du), and further in view of Zhai (Zhai et al, US20230357422A1, Priority to 9/17/2020; hereinafter Zhai), Jiang 1 (Jiang et al, “Abstract 5644: Claudin 18.2 - 4-1BB bispecific antibody induced potent tumor inhibition through tumor-specific 4-1BB activation”, 2020, Cancer Res, 80:5644; hereinafter Jiang 1), and Jiang 2 (Jiang et al, WO2021027850A1, Priority to 8/12/2019; hereinafter Jiang 2).
The applied reference, US20230357422A1, has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Regarding instant claims 16 and 18, Du teaches an anti-CLDN18.2 bispecific antibody that binds to (i) CLDN18.2 wherein the binding region consists of two pairs of polypeptide chains, wherein each pair has (1) a light chain that consists of a light chain variable region (VL) and a light chain constant region (CL), and (2) a heavy chain comprised of a heavy chain variable region (VH) and a heavy chain constant region (CH) (page 30, ¶[0559]); and (ii) a second functional module (e.g. a second antibody) having a binding specificity different from CLDN18.2, wherein the second antibody or antigen binding fragment thereof binds to any protein that can be used as a potential target for combination therapy (pages 24-25, ¶[0461]-[0465]) Du also teaches the VH of the CLDN18.2 binding region that specifically binds CLDN18.2 comprises the amino acid sequence SEQ ID NO:101, which is 99.4% identical to instant SEQ ID NO:1, wherein the HCDR1-3 are identical in both amino acid sequences as shown below:
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, and the VL of the CLDN 18.2 region comprises the amino acid sequence SEQ ID NO:92, which is 99.5% identical to instant SEQ ID NO:2, wherein there is a single amino acid difference in the LCDR1 region as shown below:
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(page 12, ¶[[0080]-[0082]; pages 11-12, ¶[0061]-[0063]). Regarding instant claim 17, Du teaches that the antibody or antigen-binding fragment thereof that specifically binds CLDN18.2 comprises a VH framework region (FR) derived from a human immunoglobulin (page 13, ¶[0129]). Regarding instant claim 20, Du teaches that the heavy chain of the antibody or antigen-binding fragment thereof that binds CLDN18.2 comprises a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof, in which the variant has a substitution, deletion or addition of 1, 2, 3, 4 or 5 amino acids, and the light chain comprises a light chain constant region (CL) of a human immunoglobulin or a variant thereof, in which the variant has a conservative substitution of one or more amino acids (page 23, ¶[0443]-0445]. Regarding instant claims 22-24, Du teaches an isolated nucleic acid molecule encoding the bispecific antibody that specifically binds CLDN18.2, a vector comprising the isolated nucleic acid molecule encoding the bispecific antibody, and a host cell comprising the isolated nucleic acid molecule that encodes the bispecific antibody (page 24, ¶[0454]-[0456]). Regarding instant claim 25, Du teaches that the bispecific antibody that binds CLDN18.2 can be linked to a therapeutic agent to form an immunoconjugate (page 25, ¶[0466]-[0468]). In regards to instant claims 26-28, Du teaches a pharmaceutical composition comprising the bispecific antibody, a pharmaceutically acceptable carrier, and a pharmaceutically active agent, wherein the pharmaceutically active agent is an antitumor agent (page 27, ¶[0503]-[0507]). In regards to instant claims 29-32, Du teaches a method for inhibiting the growth and/or killing of a tumor cell expressing CLDN18.2 comprising contacting the tumor cell with an effective amount of the CLDN18.2 bispecific antibody, wherein the method can be used for a therapeutic purpose. Du further teaches using the CLDN18.2 bispecific antibody in a method for treating a tumor in a subject comprising administering to the subject in need thereof an effective amount of the CLDN18.2 bispecific antibody, wherein the tumor involves a tumor cell expressing CLDN18.2 (pages 27-28, ¶[0515]-[0522]).
However, Du does not teach a bispecific antibody that binds CLDN18.2 and 4-1BB, wherein the 4-1BB binding entity comprises a VH CDR1 or a variant thereof, VH CDR2 or a variant thereof, and VH CDR3 or a variant thereof as set forth in instant SEQ ID NO:25. Furthermore, Du does not teach a method for inducing a cell to secrete IL-2 in a subject, wherein the method comprises administering to a subject in need thereof an effective amount of the bispecific antibody that binds CLDN18.2 and 4-1BB.
The deficiency is resolved by Zhai, Jiang 1, and Jiang 2.
Regarding instant claims 16 and 19, Zhai teaches a single domain antibody targeting 4-1BB comprising one heavy chain variable region, wherein the VHH amino acid sequence comprises the amino acid sequence SEQ ID NO:39, which is 97.7% identical to instant SEQ ID NO:25, wherein there are two amino acid differences in the HCDR3 region as shown below:
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(page 1, Abstract; page 33, ¶[0323]).
Regarding instant claim 16, Jiang 2 teaches bispecific antibodies that target both CLDN18.2 and 4-1BB, wherein the binding region that specifically binds 4-1BB is connected to the carboxy-terminus of the heavy chain of CLDN18.2 (page 1, Abstract; page 20, ¶[0071]). Regarding instant claim 21, Jiang 2 teaches that the bispecific antibody comprises a flexible linker sequence (page 24, ¶[0077]). Regarding instant claims 32-33, Jiang 2 teaches that the bispecific antibodies stimulate human peripheral blood mononuclear cell (PBMC) response by measuring IL-2 and IFN-γ, wherein only the bispecific antibodies activated PBMC response in the presence of CLDN18.2 expressing cells (pages 38-39, §3.2, ¶[0119]-[0120]; Fig. 6).
Regarding claim 16, Jiang 1 teaches CLDN18.2 is believed to be an ideal tumor antigen for immunotherapy, and the development of a bispecific antibody targeting CLDN18.2 and 4-1BB (hereinafter TJ-CD4B) showed stronger binding capability to CLDN18.2 when compared with benchmark CLDN18.2 monoclonal antibody (IMAB362). Additionally, Jiang 1 teaches that functional evaluation of TJ-CD4B indicated that the activation of 4-1BB signaling was solely dependent on CLDN18.2 expression on the cell, and TJ-CD4B showed superior 4-1BB activity than benchmark 4-1BB monoclonal antibody (urelumab) in the presence of cells expressing a wide range of CLDN18.2 levels (Introduction section).
Regarding instant claims 16-19 and 21-28, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the pharmaceutical composition comprising the bispecific antibody or nucleic acid encoding the bispecific antibody that binds to CLDN18.2 comprising SEQ ID NOs:92 and 101 (same as instant SEQ ID NOs: 1 and 2 with amino acid variations) of Du to include the 4-1BB comprising SEQ ID NO:39 of Zhai to form a pharmaceutical composition comprising a bispecific antibody that binds to both CLDN18.2 and 4-1BB or a nucleic acid encoding said bispecific antibody that binds to both CLDN18.2 and 4-1BB wherein the bispecific antibody comprises a flexible linker sequence connecting the 4-1BB binding region to the carboxy-terminus of the heavy chain of the CLDN18.2 binding region as taught by Jiang 2. This is obvious because, Du teaches a bispecific antibody that binds to CLDN18.2 comprising two pairs of polypeptide chains, wherein each pair comprises SEQ ID NOs:92 and 101, and a second antigen, wherein the antigen can be any protein different from CLDN18.2 and can be used as a potential target for combination therapy, Zhai teaches a single domain antibody targeting 4-1BB comprising one heavy chain variable region, wherein the VHH amino acid sequence comprises SEQ ID NO:39, Jiang 2 teaches bispecific antibodies that target CLDN18.2 and 4-1BB, wherein the 4-1BB binding region is connected to the carboxy-terminus of the heavy chain of CLDN18.2, and the bispecific antibody comprises a flexible linker sequence, and Jiang 1 teaches the development of TJ-CD4B, which demonstrated stronger binding capability to CLDN18.2 when compared with benchmark CLDN18.2 monoclonal antibody (IMAB362), wherein functional evaluation of TJ-CD4B indicated activation of 4-1BB signaling was solely dependent on CLDN18.2 expression on the cell. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant bispecific antibody, which comprises a CLDN18.2 binding entity and a 4-1BB binding entity wherein the CLDN18.2 binding entity comprises two pairs of identical immunoglobulin chains, wherein each pair comprises instant SEQ ID NOs:1, and 2 with amino acid variations, and the 4-1BB binding entity comprises SEQ ID NO:25 with amino acid variations, wherein the 4-1BB binding entity is connected to the C-terminus of the heavy chain of the CLDN18.2 binding entity via a peptide linker.
Regarding instant claim 20, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the bispecific antibody that binds to CLDN18.2 and 4-1BB of Du and Zhai, to comprises a VH framework region (FR) derived from a human immunoglobulin, and a heavy chain constant region (CH) of a human immunoglobulin. This is obvious because, the combined teachings of Du and Zhai teach a bispecific antibody that binds to CLDN18.2 comprising SEQ ID NOs:92 and 101 and 4-1BB comprising SEQ ID NO:39, and Du further teaches the bispecific antibody that binds to CLDN18.2 and a second antigen comprising a CH and CL of a human immunoglobulin or a variant thereof. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant bispecific antibody binds to CLDN18.2 and 4-1BB, wherein the CLDN18.2 binding entity comprises a human immunoglobulin CH or variant thereof and a human immunoglobulin CL or variant thereof.
Regarding instant claims 29-33, it would have been obvious for a person having ordinary skill in the art at the time of filing that the pharmaceutical composition comprising the bispecific antibody that binds to CLDN18.2 and 4-1BB of Du and Zhai is administered to a subject in need thereof to treat a tumor that expresses CLDN18.2 in a subject as taught by Jiang 1, wherein the bispecific antibody stimulates an IFNγ and IL-2 cytokine response as taught by Jiang 2. This is obvious because, the combined teachings of Du and Zhai teach a bispecific antibody that binds to CLDN18.2 comprising SEQ ID NOs:92 and 101 and 4-1BB comprising SEQ ID NO:39, Du teaches a method for treating a tumor in a subject comprising administering to the subject in need thereof an effective amount of the CLDN18.2 bispecific antibody, wherein the tumor involves a tumor cell expressing CLDN18.2, Jiang 1 teaches that the bispecific antibody targeting CLDN18.2 and 4-1BB, TJ-CD4B, showed stronger binding capability to CLDN18.2 when compared with benchmark CLDN18.2 monoclonal antibody, cellular CLDN18.2 expression-dependent 4-1BB activation, and superior 4-1BB activity than benchmark 4-1BB monoclonal antibody in the presence of cells expressing a wide range of CLDN18.2 levels, and Jiang 2 teaches that the anti-CLDN18.2 x anti-4-1BB bispecific antibody stimulated PBMC response when IL-2 and IFN-γ levels were measured, wherein only the bispecific antibodies activated PBMC response in the presence of CLDN18.2 expressing cells. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating a tumor in a subject comprising administering to a subject in need thereof an effective amount of the instant bispecific antibody that binds CLDN18.2 and 4-1BB, wherein the instant bispecific antibody induced a cell to secrete the cytokine IFNγ and IL-2.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Conclusion
No claims are allowed.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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