DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election with traverse of Group I (claims 1-4, 6-7, 10-12, 14, 16-17, and 23-24) and election without traverse of the below-listed species in the reply filed on 11/07/2025 is acknowledged.
Elected Species:
A bispecific antibody comprising:
Two chains;
Two binding domains, one for CD4 and a second for TGF-β1;
A CD4 binding domain comprising HCDRs 1-3, LCDRs 1-3, VH, and VL comprising an amino acid sequence of SEQ ID NOs: 53-55, 56-58, 1, and 2, respectively;
A TGF-β1 binding domain comprising HCDRs 1-3, LCDRs 1-3, VH, and VL comprising an amino acid sequence of SEQ ID NOs: 59-61, 65-67, 3, and 6, respectively;
A first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 15; and
A second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 16.
It is specifically noted that the elected bispecific antibody corresponds to the antibody with secondary identifier CT102 in the instant disclosure.
It is noted that Applicant argues the following regarding the restriction requirement in view of instantly amended claim 1:
After amendment, the cited references Li and Mishra do not teach the limitation reciting "the bispecific antibody is in a form of IgG-ScFv, and the ScFv is connected to a C-terminus of a light chain or a heavy chain of the IgG", which is now identified as the special technical feature; when the ScFv is connected to a C-terminus of a light chain of the IgG, the bispecific antibody corresponds to CT101 of the instant disclosure, and when the ScFv is connected to a C-terminus of a heavy chain of the IgG, the bispecific antibody corresponds to CT102 of the instant disclosure.
The bispecific antibodies in new claim 1 have a better affinity towards CD4 and TGF-βl and longer half-life period than 4T-Trap in Li (see results regarding CT101 and CT102 in Embodiments 4-6 of the instant specification).
The bispecific antibodies in amended claim 1 have a better inhibition effect on TGF-β signaling in CD4+ cells than CT103, CT104, CT105, CT107, CT108, CT109, CT110, CT111, and CT112; bispecific antibodies not in the form of IgG-ScFv have unsatisfactory performance (see Figures 2, 4-5, and 14 of the instant specification).
A person of skill in the art could not have expected to obtain the technical solution as claimed in proposed amended claim 1 based on the disclosure of Li when combined with Mishra; Mishra does not disclose or suggest the technical feature that "the bispecific antibody is in a form of IgG-ScFv and the ScFv is connected to a C-terminus of a light chain or a heavy chain of the IgG." Furthermore, Mishra does not disclose the binding affinities to CD4 and TGF-βl, nor does it disclose the half-life period. Therefore, it is out of expectation of a person of skill in the art to obtain the bispecific antibody in new claim 1 which have superior affinity towards CD4 and TGF-βl, inhibition effect on TGFβ signaling in CD4+ cells, and long half-life period.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
Specifically, it is noted that Applicant is arguing data from only two specific antibody species, designated as CT101 and CT102. However, it is noted that claim 1 encompasses species beyond those of just CT101 and CT102, wherein the first function region may be any antibody or antigen binding fragment thereof that targets human CD4 and/or the second function region may be any antibody or antigen binding fragment thereof that binds human TGF-β1. As such, the arguments regarding (i) the binding affinities to CD4 and TGF-βl and (ii) the half-life periods are specific to CT101 and CT102 and are therefore not commensurate in scope with the instant claims. It is further noted, that in view of newly cited US 2018/0222970 A1 (herein after referred to as “Qiu”) and non-patent literature by Orcutt et. al. (Protein Engineering, Design & Selection, 2010, 23(4), 221-228; herein after referred to as “Orcutt”) the special technical feature of amended claim 1 regarding the IgG-ScFv format is rendered obvious (further detailed in the 103 section below).
The teaching of Li are already of record, and are also presented in the 103 section below. Qiu teaches an isolated TGF-βl-binding scFv-Fc dimer that selectively binds TGF-βl wherein the scFv-Fc dimer may comprise: (i) two polypeptide monomers, each having the following formula, from N-terminal to C-terminal: (VH domain)-(linker)-(VL domain)-(hinge)-(Fc region); or (ii) a first polypeptide chain and a second polypeptide chain wherein the first and the second polypeptide chains may both have the formula of, from N-terminal to C-terminal: (VH domain)-(linker1)n -(VL domain)-(linker2)m -(hinge)p-(Fc region) wherein p may be 0 or 1, n may be 0 or 1, and m may be 0 or 1 (Paragraph 0013). Thus, Qiu discloses antibody formats specific to TGF-β1 that comprise ScFvs. More specifically, Qiu discloses the CAT191 ScFv, corresponding to SEQ ID NO: 12, which comprises: (VH domain)- SSGGGSGGGGSGGGG-(VL domain).
Orcutt discloses a bispecific antibody design with specificity to different cell surface protein targets and small molecule haptens; simultaneous binding, affinity and in vitro stability are assessed, as are in vivo blood clearance and tumor targeting (Page 221, Column 2, Paragraph 2). The bispecific format is that of the IgG-ScFv format instantly claimed, wherein the bispecific antibody comprises two polypeptide chains, wherein one polypeptide chain comprises, form N- to C-terminus, VH(Sm3e)-CH1-CH2-CH3 and the other polypeptide chain comprises, from N- to C-terminus, VL(Sm3e)-Ck-Linker-VH(C825)-Linker-VL(C825) (see Page 223, Plasmid Design; Figure 1). Thus, Orcutt supports bispecific antibody formats wherein the bispecific antibody is in a form of IgG-ScFv, and the ScFv is connected to a C-terminus of a light chain the IgG.
Li, Qiu, and Orcutt are considered to be analogous to the present invention as they are in the same field of cancer, TGF-β1, and/or bispecific antibodies. Thus, it would have been obvious to one of ordinary skill in the art that the TGF-βRII extracellular domain of the bispecific antibody of Li could be substituted with a TGF-β1 ScFv of Qiu, wherein the bispecific antibody could be modified to the IgG-ScFv format of Orcutt because the combination of prior art elements would be expected to obtain predictable results with a reasonable expectation of success; the bispecific antibody format of Orcutt comprising a CD4 and TGF-β1 targeting domains as suggested by Li, wherein the TGF-β1 targeting domain is of an ScFv format as suggested by Qiu, would still be expected to function and effectively target both CD4 and TGF-β1 which would be a therapeutic option for the treatment of cancer.
In view of the above, the Restriction/Election requirement is maintained and is made FINAL.
Claim Status
Claims 5-6, 8-9, 13, 15, and 18 have been cancelled and claims 1 and 25-26 have been amended, as requested in the amendment filed on 11/07/2025. Following the amendment, claims 1-4, 7, 10-12, 14, 16-17, and 19-26 are pending in the instant application.
Claims 19-22 and 25-26 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions in the Response filed 11/07/2025, there being no allowable generic or linking claim.
Claims 1-4, 7, 10-12, 14, 16-17, and 23-24 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, the claim to foreign priority has not been perfected as no English translation of the priority document has been provided.
Claims 1-4, 7, 10-12, 14, 16-17, and 23-24 have an effective filing date of June 25, 2021 corresponding to PCT/CN2021/102428, as the claim to foreign priority has not been perfected.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/16/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because Figures 2, 8-9, and 19 comprise text/labels that are blurry and difficult to read. Further regarding Figure 19, it is noted that the figure label is not the same orientation as the figure. 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 use of, for example, the terms HiTrap, HisTrap, DVD-Ig, CrossMab, Biacore (various software), FACS, SoftMax Pro, Superdex, AKTA, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
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 14 is objected to because of the following informalities: claim 14 lists limitations in a list using "a.", "b.", "c.", etc. The claim therefore includes periods that do not designate an abbreviation or the end of a sentence. This objection can be obviated by amending the claim such that the list uses “a)”, “(a)”, or something similar. Appropriate correction is required.
Claims 23-24 are objected to because of the following informalities: claims 23-24 recite “detectable mark” but should read “detectable marker”. Appropriate correction is required.
Claim Interpretation
It is specifically noted that claims that refer to sequence limitations that recite “an amino acid sequence” of a recited SEQ ID NO. are interpreted as including the full-length sequences and fragments of the recited SEQ ID NOs. For example, HCDR1 having an amino acid sequence of SEQ ID NO:53 may include the full-length sequence corresponding to SEQ ID NO:53 or any fragment thereof comprising at least two consecutive amino acids.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 7, 10-12, 14, 16-17, and 23-24 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.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The claims are drawn to a genus of bispecific antibodies comprising at least a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises partial or complete structure of a first function region, and/or, partial or complete structure of a second function region; wherein the first function region targets human protein cluster of differentiation 4 (CD4), and is an anti-CD4 antibody or an antigen-binding fragment thereof; wherein the second function region targets human protein transformation growth factor-β1 (TGF-β1), and is an anti-TGF-β1 antibody or an antigen-binding fragment thereof; wherein the bispecific antibody is in a form of IgG-ScFv, and the ScFv is connected to a C-terminus of a light chain or a heavy chain of the IgG (see claim 1). At Paragraphs 00145-00166, one species of the first function region targeting human CD4 has been adequately described (by sequences of the VH, VL, HCR1-3, and LCDR1-3), and three species of the second function region targeting human TGF-β1 have been adequately described (by sequences of the VH, VL, HCR1-3, and LCDR1-3). These function regions, and thus a bispecific antibody comprising said function regions, have been adequately described by the recitation of six CDRs per function region. However, even though Applicant has disclosed species of bispecific antibodies that target both human CD4 and human TGF-β1, Applicant is claiming a large and structurally diverse genus of bispecific antibody species, wherein the function regions of said bispecific antibody are described by function only. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed. Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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; and see Enzo Biochem, Inc. V. Gen-Probe Inc. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As previously indicated, Applicant has disclosed three species within the genus claimed. However, given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of said numerous adequately described species is not sufficiently representative of the entire genus.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members.
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Since there are only a few presented sequences taught by Applicant responsible for the function of the recited function domains of the genus of bispecific antibodies, and such sequences are not required by the claims, and additional bispecific antibodies would vary in structure, there is no correlation between structure and function between the members of the recited or any peptide genus. Thus, since there is no correlation between structure and function across the entire genus, functional language should not be used to define the genus. Rather, structure should be used, including the conserved sequences required for said function.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since the genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus.
Applicant has not disclosed relevant, identifying characteristics of CDR amino acid sequences (and/or combinations thereof) that confer upon the function regions of a bispecific antibody the ability to bind human CD4 and human TGF-β1. It is well-known in the art that antibody binding domains generally comprise six CDRs (HCDRs1-3 and LCDRs1-3). The amino acid sequences of the CDRs are hypervariable, and the amino acid residues contained within the six CDRs determine the antigen specificity of a particular antibody. Absent a description of the at least minimal structural features correlating with a functional ability to bind human CD4 or human TGF-β1 which are shared by members of a genus of bispecific antibodies comprising function regions that commonly share these functions, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which CDR amino acid sequences may be combined such that the resultant bispecific antibody comprises two function regions, each of which comprise six CDRs that confer the ability to bind human CD4 or human TGF-β1.
Although screening techniques can be used to isolate bispecific antibodies that possess the ability to bind human CD4 and human TGF-β1, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Further regarding claims 2, 4, 12, and 14, it is noted that the claims do comprise sequences, however the sequence limitations are drawn to “an amino acid sequence” of a recited SEQ ID NO. As such, the sequence limitations are being interpreted as including the full-length sequences and fragments of the recited SEQ ID NOs. For example, HCDR1 having an amino acid sequence of SEQ ID NO:53 may include the full-length sequence corresponding to SEQ ID NO:53 or any fragment thereof comprising at least two consecutive amino acids. As detailed above, the only adequately described species of the instant disclosure comprise six full-length CDRs per function region and Applicant has not disclosed relevant, identifying characteristics of CDR amino acid sequences (and/or combinations thereof) that confer upon the function regions of a bispecific antibody the ability to bind human CD4 and human TGF-β1 such that fragments of the adequately described CDRs would have a conserved structure corresponding to the functions of being able to bind human CD4 and human TGF-β1.
Claims 1, 3, 7, 10-11, 16-17, and 23-24 are included in this rejection as they depend from and/or incorporate the bispecific antibody of claim 1.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 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 claims 10, 16, and 23, the phrase "preferably" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In claim 10 it is unclear if the peptide linker must be GGGGS. In claim 16 it is unclear if Kd values must be acquired through a Biacore Molecular Interaction System. In claim 23 it is unclear if the conjugate reagent must be a chemical molecule, fluorescent substance, luminescent substance, colored substance, or an enzyme.
Claim 16 further contains the trademark/trade name Biacore. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a system for determining/measur and, accordingly, the identification/description is indefinite.
With regard to claims 2, 4, 12, and 14, the claims recite “an amino acid sequence” of a recited SEQ ID NO. when referencing sequence limitations. As such, it is unclear as to if the intended scope with regard to the recited SEQ ID NOs is intended to be the full-length sequences or includes fragments thereof. Therefore, claims 2, 4, 12, and 14 are considered to be indefinite. As noted above, for the purpose of examinations the claims are being interpreted as including the full-length sequences and fragments of the recited SEQ ID NOs. For example, HCDR1 having an amino acid sequence of SEQ ID NO:53 may include the full-length sequence corresponding to SEQ ID NO:53 or any fragment thereof comprising at least two consecutive amino acids.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 3 fails to further limit the claim from which it depends. Claim 1 recites that the bispecific antibody is of the IgG-ScFv format, which requires that one of the recited function regions is an IgG and the other is an scFv. Claim 3 recites function regions having structures beyond those required by claim 1, from which claim 3 depends, and therefore fails to further limit claim 1; claim 3 is broader than claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
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 1-4, 7, 10-12, 14, 16-17, and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Li et. al. (Nature, 2020, 587(7832), 121-125; previously cited on PTO-892; herein after referred to as "Li") in view of US 2018/0222970 A1 (herein after referred to as "Qiu") and non-patent literature by Orcutt et. al. (Protein Engineering, Design & Selection, 2010, 23(4), 221-228; herein after referred to as "Orcutt") as evidenced by US 2014/0294759 A1 (herein after referred to as “Chu”)
Li teaches that blocking TGF-β signaling in CD4+ T cells remodels the tumor microenvironment and restrains cancer progression; the authors engineered a bispecific receptor decoy by attaching the TGF-β-neutralizing TGF-βRII extracellular domain to ibalizumab, a non-immunosuppressive CD4 antibody, naming it CD4 TGF-β Trap (4T-Trap) wherein compared to a non-targeted TGF-β-Trap, 4T-Trap selectively inhibited Th cell TGF-β signaling in tumor-draining lymph nodes, causing tumor vasculature reorganization and cancer cell death, a process dependent on the Th2 cytokine interleukin-4 (IL-4) (Abstract). Thus, Li teaches a bispecific antibody that targets both TGF-β signaling and CD4, wherein it is noted that the TGF-β-neutralizing TGF-βRII extracellular domain binds TGF-β1 (see for example page 3, paragraph 2).
However, it is noted that the domain of the bispecific antibody of Li that binds TGF-β1 is a TGF-βRII extracellular domain, not an antibody or antigen binding fragment thereof. This deficiency is remedied by Qiu.
Qiu teaches an isolated TGF-βl-binding scFv-Fc dimer that selectively binds TGF-βl wherein the scFv-Fc dimer may comprise: (i) two polypeptide monomers, each having the following formula, from N-terminal to C-terminal: (VH domain)-(linker)-(VL domain)-(hinge)-(Fc region); or (ii) a first polypeptide chain and a second polypeptide chain wherein the first and the second polypeptide chains may both have the formula of, from N-terminal to C-terminal: (VH domain)-(linker1)n -(VL domain)-(linker2)m -(hinge)p-(Fc region) wherein p may be 0 or 1, n may be 0 or 1, and m may be 0 or 1 (Paragraph 0013). Thus, Qiu discloses antibody formats specific to TGF-β1 that comprise ScFvs. More specifically, Qiu discloses the CAT191 ScFv, corresponding to SEQ ID NO: 12, which comprises: (VH domain)- SSGGGSGGGGSGGGG-(VL domain).
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Orcutt discloses a bispecific antibody design with specificity to different cell surface protein targets and small molecule haptens; simultaneous binding, affinity and in vitro stability are assessed, as are in vivo blood clearance and tumor targeting (Page 221, Column 2, Paragraph 2). The bispecific format is that of the IgG-ScFv format instantly claimed, wherein the bispecific antibody comprises two polypeptide chains, wherein one polypeptide chain comprises, form N- to C-terminus, VH(Sm3e)-CH1-CH2-CH3 and the other polypeptide chain comprises, from N- to C-terminus, VL(Sm3e)-Ck-Linker-VH(C825)-Linker-VL(C825) (see Page 223, Plasmid Design; Figure 1, reproduced below).
Thus, Orcutt supports bispecific antibody formats wherein the bispecific antibody is in a form of IgG-ScFv, and the ScFv is connected to a C-terminus of a light chain the IgG.
Li, Qiu, and Orcutt are considered to be analogous to the present invention as they are in the same field of cancer, TGF-β1, and/or bispecific antibodies. Thus, it would have been obvious to one of ordinary skill in the art that the TGF-βRII extracellular domain of the bispecific antibody of Li could be substituted with a TGF-β1 ScFv of Qiu, wherein the bispecific antibody could be modified to the IgG-ScFv format of Orcutt because the combination of prior art elements would be expected to obtain predictable results with a reasonable expectation of success; the bispecific antibody format of Orcutt comprising a CD4 and TGF-β1 targeting domains as suggested by Li, wherein the TGF-β1 targeting domain is of an ScFv format as suggested by Qiu, would still be expected to function and effectively target both CD4 and TGF-β1 which would be a therapeutic option for the treatment of cancer.
With regard to claims 2 and 4, the bispecific antibody of claim 1 is rendered obvious by Li, Qiu, and Orcutt. It is further noted that the ScFv corresponding to CAT191 disclosed by Qiu corresponds to SEQ ID NO: 12; it is noted that Qiu SEQ ID NO: 12 residues 1-123 are a 100% match to instant SEQ ID NO: 3 and further comprise 100% matches to instant SEQ ID NOs: 59-61 whereas residues 139-245 are a 100% match to instant SEQ ID NO: 6 and further comprise 100% matches to instant SEQ ID NOs: 65-67. However, it is noted that the cited references do not explicitly teach instant SEQ ID NOs: 53-55 and 56-58, nor instant SEQ ID NOs: 1 and 2, with regard to the first function region specific to human CD4. However Chu discloses the sequences corresponding to ibalizumab as used in the bispecific antibody of Li.
Chu discloses the heavy chain and light chain sequences of ibalizumab, corresponding to Chu SEQ ID NOs: 10 and 11, respectively. It is noted that residues 1-122 of Chu SEQ ID NO: 10 are a 100% match to instant SEQ ID NO: 1 and further comprise 100% matches to instant SEQ ID NOs: 53-55 whereas residues 1-112 of Chu SEQ ID NO: 11 are a 100% match to instant SEQ ID NO: 2 and further comprise 100% matches to instant SEQ ID NOs: 56-58. Thus, the sequences corresponding to ibalizumab, as utilized by Li, were known and publicly available at the time of the instant invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 3, it is noted that in the bispecific antibody format disclosed by Orcutt, shown above, one of the function regions is an ScFv and the other is an IgG. Additionally, it is noted that the anti-CD4 of Li is ibalizumab, a humanized IgG4 antibody, and the TGF-β1 targeting region of the antibody constructs of Qiu are of ScFv formats, as exemplified by the CAT191 ScFv represented by Qiu SEQ ID NO: 12. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 7, it is noted that the bispecific antibody of Li and the bispecific antibody format of Li include one function region to a first antigen and one function region to a second antigen (i.e., the number of the first and second function regions are independently 1). More specifically, Li discloses a bispecific antibody comprising a single function region specific to CD4 and a single second function region specific to TGF-β1 whereas the bispecific format of Orcutt comprises a single first function region to Sm3e and a single second function region to C825; though it is noted that the full assembled bispecific antibody of Orcutt (a homodimer of the recited heavy/light chain polypeptides) comprises two total first function regions to Sm3e and two total second function region to C825 (see Figure 1 reproduced above). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 10-11, Orcutt discloses a bispecific antibody design with specificity to different cell surface protein targets and small molecule haptens; simultaneous binding, affinity and in vitro stability are assessed, as are in vivo blood clearance and tumor targeting (Page 221, Column 2, Paragraph 2). The bispecific format is that of the IgG-ScFv format instantly claimed, wherein the bispecific antibody comprises two polypeptide chains, wherein one polypeptide chain (i.e., the heavy chain polypeptide) comprises, form N- to C-terminus, VH(Sm3e)-CH1-CH2-CH3 (corresponding to the formula of the instantly claimed second polypeptide chain) and the other polypeptide chain (i.e., the light chain polypeptide) comprises, from N- to C-terminus, VL(Sm3e)-Ck-Linker-VH(C825)-Linker-VL(C825) (corresponding to the formula of the instantly claimed first polypeptide chain) (see Page 223, Plasmid Design; Figure 1, reproduced above). It is further noted that the linkers disclosed by Orcutt are of the formula (Gly4Ser)2 and (Gly4Ser)3, respectively. Additionally, it is noted that the light chain and heavy chain polypeptide chains interact to form a polypeptide group (i.e., a bispecific half-antibody molecule) wherein two polypeptide groups together form a homodimer (i.e., a full bispecific antibody molecule) (see Figure 1, reproduced above). Thus, the bispecific format of Orcutt matches the instantly claimed first and second polypeptide formulas of instant claim 10 wherein the polypeptides of instant claim 10 may interact to form polypeptide groups which may further interact to form a homodimer. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 12, the bispecific antibody of claim 10 is rendered obvious by Li, Qiu, and Orcutt. It is further noted that the ScFv corresponding to CAT191 disclosed by Qiu corresponds to SEQ ID NO: 12; it is noted that Qiu SEQ ID NO: 12 residues 1-123 are a 100% match to instant SEQ ID NO: 3 and further comprise 100% matches to instant SEQ ID NOs: 59-61 whereas residues 139-245 are a 100% match to instant SEQ ID NO: 6 and further comprise 100% matches to instant SEQ ID NOs: 65-67. However, it is noted that the cited references do not explicitly teach instant SEQ ID NOs: 53-55 and 56-58, nor instant SEQ ID NOs: 1 and 2, with regard to the first function region specific to human CD4. However Chu discloses the sequences corresponding to ibalizumab as used in the bispecific antibody of Li.
Chu discloses the heavy chain and light chain sequences of ibalizumab, corresponding to Chu SEQ ID NOs: 10 and 11, respectively. It is noted that residues 1-122 of Chu SEQ ID NO: 10 are a 100% match to instant SEQ ID NO: 1 and further comprise 100% matches to instant SEQ ID NOs: 53-55 whereas residues 1-112 of Chu SEQ ID NO: 11 are a 100% match to instant SEQ ID NO: 2 and further comprise 100% matches to instant SEQ ID NOs: 56-58. Thus, the sequences corresponding to ibalizumab, as utilized by Li, were known and publicly available at the time of the instant invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 14, it is specifically noted that instant SEQ ID NO: 15 comprises instant SEQ ID NOs: 2 (CD4 VL), 9 (IgG4 kappa light chain constant region), 3 (TGF-β1 VH), and 6 (TGF-β1 VH) and instant SEQ ID NO: 16 comprises instant SEQ ID NOs: 1 (CD4 VH), 10 (IgG4 CH1 domain), 11 (IgG4 hinge with S228P mutation), and 12 (IgG4 Fc domain). It is further noted that the ScFv corresponding to CAT191 disclosed by Qiu corresponds to SEQ ID NO: 12; it is noted that Qiu SEQ ID NO: 12 residues 1-123 are a 100% match to instant SEQ ID NO: 3 and further comprise 100% matches to instant SEQ ID NOs: 59-61 whereas residues 139-245 are a 100% match to instant SEQ ID NO: 6 and further comprise 100% matches to instant SEQ ID NOs: 65-67. Chu discloses the sequences corresponding to ibalizumab as used in the bispecific antibody of Li wherein: (i) residues 1-122 of Chu SEQ ID NO: 10 are a 100% match to instant SEQ ID NO: 1 and further comprise 100% matches to instant SEQ ID NOs: 53-55; and (ii) residues 1-112 of Chu SEQ ID NO: 11 are a 100% match to instant SEQ ID NO: 2 and further comprise 100% matches to instant SEQ ID NOs: 56-58. Additionally it is noted that the bispecific format of Orcutt is that of the IgG-ScFv format instantly claimed in claim 10. Thus, the bispecific antibody of claim 10 resulting from the combination of Li, Qiu, and Orcutt, as evidenced by Chu, would comprise: a first polypeptide comprising instant SEQ ID NOs: 2, 3, and 6 and a second polypeptide comprising instant SEQ ID NO: 1. It is specifically noted that claim recites “an amino acid sequence” of recited SEQ ID NOs: 15 and 16, which is interpreted as including the full-length sequences and fragments thereof comprising at least two consecutive amino acids. Thus, under BRI the claim limitations are met by the combination of Li, Qiu, and Orcutt as evidenced by Chu. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 16-17, it is noted that the bispecific antibody of Li exhibited a Kd of 0.1 nM for CD4 (see Page 3, First Full Paragraph) as determined by surface plasmon resonance (see Page 9, Surface Plasmon Resonance), and neutralized TGF-β1 with an IC80 at 1.3 nM (see Page 3, First Full Paragraph) as determined by a luciferase signaling reporter assay (see Page 10, Luciferase Reporter Assays). Additionally, it is noted that Qiu also discloses data regarding Kd and IC50 data of the TGF-β1 antibody formats disclosed by the invention, wherein Figure 3 indicates that the IC50 of CAT191 ScFv is between 0.1-1 nM, while the CAT191 ScFv further comprising an Fc domain has an IC50 of between 0.001-0.01 nM (see Sheet 3) as determined by A549 cell-based potency assays (see Paragraph 0099) and the CAT191 ScFv had Kd values ranging from 1.3-1.7 nM while the CAT191 ScFv further comprising an Fc domain had Kd values ranging from 0.09-0.5 nM as determined by surface plasmon resonance (see Page 10, Table 2). The instantly claimed bispecific antibody would be expected to have similar properties to that of Li, wherein even if an ScFv format for the TGF-β1 function region was that of Qiu instead of the extracellular domain disclosed by Li, the Kd value would still reasonably be expected to be below 1 nM for both CD4 and TGF-β1 taking into consideration the trends observed by Qiu (wherein the inclusion of an Fc domain enhances the properties of the ScFv). Furthermore, the IC50 with regard to neutralizing TGF-β1 would also be expected to be <5 nM, as all observed IC50 values across Li and Qiu were below 5 nM. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 23-24, Qiu further discloses that surface residues of variable domains can be substituted with Cys or Lys residues, for example, which then can be covalently modified and coupled to molecules conferring useful characteristics to the antibodies or antigen-binding fragments thereof (e.g., a detectable label, toxin, targeting moiety, or protein) (Paragraph 0056). Detectable labels include: (i) radio labels such as 131I or 99Tc, which may be attached to antibodies or antigen-binding fragments thereof using methods known in the art; (ii) enzyme labels such as horseradish peroxidase; and/or (iii) chemical moieties such as biotin which may be detected via binding to a specific cognate detectable moiety, e.g., labeled avidin (Paragraph 0057). Additionally, Qiu discloses pharmaceutical compositions comprising the ScFv formats of the invention, wherein the pharmaceutical compositions may comprise a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art wherein such materials should be non-toxic and should not interfere with the efficacy of the active ingredient (i.e., anti-TNF-β1 ScFv formats) (Paragraph 0088). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Conclusion
Claims 1-4, 7, 10-12, 14, 16-17, and 19-26 are pending. Claims 19-22 and 25-26 are withdrawn. Claims 1-4, 7, 10-12, 14, 16-17, and 23-24 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642