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 .
Status of Application, Amendments and/or Claims
The amendment and Applicant’s arguments, filed 29 April 2025, have been entered in full. Claims 1, 4, 5, 10-12, 24-28 are withdrawn from consideration as being drawn to a non-elected invention. Claims 2, 3, 6-9, 13, 14, 16, 17, 30 and 31 are canceled. Claims 15, 18-23 and 29 are amended. Claims 15, 18-23 and 29 are under examination.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 29 April 2025 and 31 July 2025) were received and comply with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. They have been placed in the application file and the information referred to therein has been considered as to the merits.
Withdrawn Objections And/Or Rejections
The rejection to claims 15, 18-23 and 29 under 35 U.S.C. 112(6) or 35 U.S.C. 112 (pre-AlA), second paragraph, as set forth at pages 4-6 of the previous Office Action (29 November 2024), is withdrawn in view of the amendment (29 April 2024).
The rejection to claims 15, 18-23 and 29 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AlA), first paragraph, written description, new matter, as set forth at pages 6-9 of the previous Office Action (29 November 2024), is withdrawn in view of the amendment (29 April 2024).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
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.
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.
Claims 15, 18-23 and 29 remain rejected under 35 U.S.C. 103 as being unpatentable over Johnson et al. (US 2019/0161548; published 30 May 2019, priority date 14 December 2015) in view of Brinkmann et al. (US 2010/0081796; published April 1, 2010) and Carter et al. (US 2018/0177873; published June 28, 2018, priority date April 24, 2015).
The basis for this rejection is set forth in the previous Office Action (29 November 2024, pages 9-15).
APPLICANT’S ARGUMENT ONE
Applicant argues that claim 15 recites that the VH2 and VL2 domains of the claimed engineered antibody comprises both cysteine substitutions and charged residues which form a disulfide bond and electrostatic interaction, respectively. Applicant directs the Examiner’s attention to FIG. 4 of the instant application.
Applicant argues that Johnson does not teach an engineered antibody comprising both the cysteine substitution and the charged residue substitution within one pair of the VH-VL domains (i.e., substitutions within VH2 and VL2), not to mention the specific positions for the substitutions. Applicant argues that although Johnson teaches a trivalent binding molecule comprising two VH-VL domains (i.e., VH1 and VL1, VH2 and VL2). Johnson does not teach or suggest an engineered antibody comprising both the cysteine substitutions and the charged residue substitutions within a pair of variable regions i.e., the VH2 and the VL2 domains, as required by the claims.
Applicant argues that the cysteine residues and/or the charged residues in Johnson are all located outside variable domains. Applicant directs the Examiner’s attention to the bold arrow in Fig. 6A (reproduced in Table 1 of the arguments) and paragraphs [0079], [163], [0165], Figure 3A, Figure 3B, Figure 6A, Figure 6B of Johnson. Applicant argues that Johnson discloses that, in lieu of the CH1 domain or in lieu of the CL domain, a separate peptide having the sequence of hinge (containing a cysteine residue) can be employed (para [0170] of Johnson), which further supports that the substitutions are outside of VH and VL.
Applicant argues that there is no teaching or suggestion in Johnson that would motivate a person skilled in the art to make an engineered antibody comprising any cysteine substitutions and charged substitutions within a pair of variable regions, such as VL2 and VH2, not to mention at the specified positions (e.g. position 100 of VL2 and position 44 of VH2).
Applicant’s arguments have been fully considered but are not found persuasive for the following reasons:
One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In the instant case, the Office action states Johnson teaches the engineered antibody as described in claim 15. The Office Action states Johnson teaches cysteine resides can be added in the engineered antibody to permit disulfide bonds (such as in a linker peptide).
The Office action states Johnson does not teach that cysteine residues are added at positions 44 and 100 (or positions 43 and 105) in the engineered antibody. The Office action states Johnson does not teach substitutions at positions 38 or 39 (with positively or negatively charged amino acids).
Brinkmann teaches cysteine substitutions at positions 44 of VH and 100 of VL (or positions 43 and 105). Carter teaches charged substitutions at Q39 and Q38.
APPLICANT’S ARGUMENT TWO
Applicant argues that the bispecific antibody structures disclosed by Brinkmann and Carter differ significantly from that of Johnson, and also differ significantly from each other. Applicant maintains that a person of ordinary skill in the art would not be motivated to modify Johnson in view of Brinkmann and Carter. Applicant compares the differences using schematic drawings of Johnson, Brinkmann and Carter (reproduced in Table 2 of the arguments). Applicant argues neither Brinkmann nor Carter disclose the two VH-VL domains of Johnson. Applicant argues Johnson teaches a multi-specific antibody with two VH-VL domains where the VL2 is covalently linked to the VH1, and the VL1 is covalently linked to the VH2, and where cysteine residues used to covalently link VL and VH are introduced to a separate linker outside the VH and VL domains.
Applicant argues that Brinkmann discloses an engineered antibody comprising a full-length antibody binding to a first antigen linked to a single chain Fv (scFv) fragment (or a single-chain Fab (scFab) that binds to a second antigen, where cysteine residues are introduced into the VH and VL within scFv or scFab. Applicant argues that Carter discloses a multi-specific antibody comprising a classic antibody structure with VH, CH1, VL and CL, where oppositely charged residues are introduced into VH and VL within the Fab domain (emphasis added).
Applicant argues that this is in direct contrast to the antibody design of Johnson, which introduces cysteine residues between two polypeptide chains and outside the VH and VL domains. Brinkmann discloses the substitution of cysteine residues located within VH and VL domain in a scFv or scFab. Carter disclosed substitution of oppositely charged residues located within VH and VL domains of Fab.
Applicant submits that there is no teaching, suggestion or motivation to modify Johnson with the mutations used by Brinkmann or Carter in a completely different antibody structure.
Applicant’s arguments have been fully considered but are not found persuasive for the following reasons:
Johnson teaches the invention is directed to bispecific molecules (e.g., diabodies, bispecific antibodies, trivalent binding molecules, etc.) that possess at least one epitope-binding site that is immunospecific for an epitope (abstract). Johnson teaches a diabody being a covalently bonded complex that comprises two, three, four or five polypeptide chains or a trivalent binding molecule, the trivalent binding molecule being a covalently bonded complex that comprises three, four, five, or more polypeptide chains (paras 0023-0028).
Johnson teaches the design of a diabody is based on the antibody derivative known as a single-chain Variable Domain fragment (scFv). Such molecules are made by linking Light and/or Heavy Chain Variable Domains using a short linking peptide (para 0145). Johnson teaches that FIGS. 6A-6F provide schematics of representative Fc Region-containing trivalent binding molecules having three epitope-binding sites. FIGS. 6A and 6B, respectively, illustrate schematically the domains of trivalent binding molecules comprising two diabody-type binding domains and a Fab-type binding domain . Such bispecific trivalent binding molecules comprise three epitope-binding sites, two of which are Diabody-Type Binding Domains, which provide binding Site A and binding Site B, and one of which is a Fab-Type Binding Domain (or an scFv-Type Binding Domain), which provides binding Site C (paras 0084, 0181-0184).
Contrary to the presented arguments, the engineered antibody taught by Johnson comprises scFv and scFab. As was stated in the previous Office Action, Brinkmann and Carter provide the motivation to make the substitutions because of stable dimerization, higher expression, higher production, higher heavy chain/light chain pairing and better assembly of the engineered antibody.
APPLICANT’S ARGUMENT THREE
Applicant argues that Johnson cannot be combined with Brinkmann due to Johnson teaching away. Applicant maintains that in addition to lack of teaching, suggestion and motivation to combine Johnson, Brinkmann and Clark to produce the engineered antibody of the present invention, the teaching of Johnson would discourage a person of ordinary skill in the art from introducing cysteine residue mutations disclosed in Brinkmann.
Applicant submits that Johnson designs two VH-VL domains within its antibodies to prevent binding between VH1-VL2 and VH2-VL1 pairs on the same polypeptide chain. Such prevention is achieved by using a separate short linker that ensures the VH and VL domains on the same polypeptide chain cannot associate. Applicant cites Johnson:
“….the length of the intervening linker peptide (Linker 1, which separates such VL and VH Domains) is selected to substantially or completely prevent the VL and VH Domains of the polypeptide chain from binding to one another (for example consisting of from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 intervening linker amino acid residues). Thus, the VL and VH Domains of the first polypeptide chain are substantially or completely incapable of binding to one another. Likewise, the VL and VH Domains of the second polypeptide chain are substantially or completely incapable of binding to one another. A preferred intervening spacer peptide (Linker 1) has the sequence (SEQ ID NO:5): GGGSGGGG” (para 0162).
Applicant argues that in contrast, Brinkmann promotes VH-VL binding on the same chain by introducing cysteine mutations (e.g., VH44/VL100) to create disulfide-stabilized single chain Fvs (scFvs) or scFabs. Applicant cites Brinkmann:
“..we introduced single cysteine replacements within VH and VL of the scFv at defined positions (positions VH44/VL100 according to the Kabat numbering scheme). These mutations enable the formation of stable interchain disulfides between VH and VL, which in turn stabilize the resulting disulfide-stabilized scFv module.”
Applicant argues that a skilled person in the art would be discouraged from applying Brinkmann’s stabilizing cysteine mutations to Johnson’s two VH-VL domains, as it would directly contradict Johnson’s teaching on preventing VH-VL pairing on the same polypeptide chain.
Applicant’s arguments have been fully considered but are not found persuasive for the following reasons:
1. Paragraph 0162 of Johnson pointed out by Applicant is referring to the diabodies or trivalent binding molecules comprising four polypeptide chains wherein:
first polypeptide chain comprises VL2-linker-VH1
second polypeptide chain comprises VL1-linker-VH2
The first polypeptide chain comprises a variable light domain that recognizes epitope 2 (VL2) and a variable heavy domain that recognizes epitope 1 (VH1).
The second polypeptide chain comprises a variable light domain that recognizes epitope 1 (VL1) and a variable heavy domain that recognizes epitope 2 (VH2).
Johnson does not want VL2 binding to VH1 or VL1 to binding to VH2, hence the use of the short linker. The linkers are used to keep VL2 from binding to VH1 and to keep VL1 from binding to VH2.
Johnson does this because the desired effect is the binding/interaction between the domains that recognize the same antigen; VL2 with VH2 and VL1 with to VH1.
Using the teachings of Brinkmann (cysteine substitutions in heavy chain variable domain position 44 and light chain variable domain position 100 or heavy chain variable domain position 105 and light chain variable domain position 43), enables the formation of stable disulfides between VH and VL, which in turn stabilize the resulting disulfide-stabilization.
Contrary to the presented arguments, the teaching of Johnson would not discourage a person of ordinary skill in the art from introducing cysteine residue mutations disclosed in Brinkmann.
APPLICANT’S ARGUMENT FOUR
Applicant argues that there is no teaching, suggestion or motivation to selectively modify VH2 and VL2 of the two VH-VL domains disclosed in Johnson or to combine cysteine mutations at VL2(100)/VH2(44) or VL2(43)/VH2(105) and with oppositely charged amino acid residues at VL2(44)/VH2(103) or VL2(38)/VH2(39). Applicant argues that Johnson neither discloses nor suggests modifying either pair of VH/VL domains in their two VH-VL domains. Applicant argues that Brinkmann and Carter cannot remedy this deficiency. Brinkmann and Carter each address only a single VH/VL pair—stabilized by a disulfide bond (Brinkmann) or electrostatic interactions (Carter).
Applicant argues that even if assuming, arguendo, disclosures of Johnson, Brinkmann. and Carter were combined, there would be no reasonable expectation of success. Applicant argues that the Inventors of the present application have tested different types of mutations at VH1/VL1 interface, VH2/VL2 interface, or both, and provided evidence that while certain mutations are known to stabilize polypeptide chains with VH and VL, they may not work the same way in different antibody constructs or at different parts of the construct.
Applicant states, as summarized in the request for continued examination as filed on April 17, 2024 (reproduced in Table 3), the stability is relatively low (i.e. from 61.4% to 87.9% on Day 1) in samples having oppositely charged residues at VL 38 and VH 39 but no cysteine mutations (e.g. Samples #7 and #11), and sample having cysteine mutations at VL100C and VH44C but no oppositely charged residues (e.g. Sample #3).
Applicant submits that combining mutations can also lead to unpredictability. Sample #11, which has a combination of: oppositely charged residues at VL1 38 and VH1 39, Oppositely charged residues at VL2 38 and VH2 39, and VL2 Y87W and VH2 L45A,
showed lower stability than Sample #7 (61.4% vs 73.3%), which only had oppositely charged residues at VL2 38 and VH2 39.
Applicant argues that the claimed engineered antibodies exhibit unexpected effects in stability and purity when the VL2 and VH2 domains are covalently linked via a disulfide bond formed between cysteine substitutions at the specified positions, and associate via oppositely charged residues at the specified positions.
Applicant states that as summarized (reproduced as Table 3 above), the engineered antibodies such as #9, #40, #25, #43, #44, #45, #38 and #39 (see rectangular boxes) consistently showed purity and stability of over 95%, and in some cases, over 99%, and these antibodies all have the VL2 and the VH2 covalently linked via a disulfide bond formed between 100C and 44C or between 43C and 105C, and oppositely charged residues between VL2 38 and VH2 39 or between VL2 44 and VH2 103.
Applicant argues that in contrast, antibodies such as #3, #7 and #11 (highlighted in oval boxes), lacking this disulfide bond covalently linking the VL2 and the VH2 and the oppositely charged residues, exhibited significantly lower purity and stability, falling below 90% or even below 70%.
Applicant argues that the stability and purity of antibodies #9, #40, #25, #43, #44, #45, #38 and #39 (which have the disulfide bond covalently linking the VL2 and VH2) are superior to antibody #3 (which has the disulfide bond covalently linking the VL1 and VH1 while lacking the disulfide bond covalently linking the VL2 and the VH2).
Applicant maintains that these comparative data clearly demonstrate that, when the engineered antibodies have cysteine substitutions at VL2 100 and VH2 44 or VL2 43 and VH2 105, such engineered antibodies consistently showed unexpectedly high stability and purity. This makes the claimed engineered antibodies particularly advantageous for manufacture and process development, and may be “efficiently expressed and purified using traditional procedures.” See, e.g., the application as filed at [0105].
Applicant’s arguments have been fully considered but are not found persuasive for the following reasons:
1. The Examiner has already discussed how the engineered antibody taught by Johnson comprises scFv and scFab. Brinkmann teaches the substitution of cysteine residues located within VH and VL domain in a scFv or scFab. Carter disclosed substitution of oppositely charged residues located within VH and VL domains of Fab.
2. Applicant’s arguments that the claimed engineered antibodies exhibit unexpected effects in stability and purity when the VL and VH domains are covalently linked via a disulfide bond formed between cysteine substitutions at the specified positions and associate via oppositely charged residues at the specified positions, are not found persuasive.
Both Brinkmann and Carter teach the importance of cysteine substitutions at positions 44 of VH and 100 of VL and charged substitutions at Q39 and Q38, respectively, for stable dimerization, higher expression, higher production, higher heavy chain/light chain pairing and better assembly of the engineered antibody.
3. Applicant’s argument that there is no teaching, suggestion or motivation to selectively modify VH2 and VL2 of the two VH-VL domains disclosed in Johnson is not found persuasive.
One skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense (see MPEP 2145).
MPEP 2143 teaches: The mere existence of a large number of options does not in and of itself lead to a conclusion of nonobviousness. Where the prior art teachings lead one of ordinary skill in the art to a narrower set of options, then that reduced set is the appropriate one to consider when determining obviousness using an obvious to try rationale.
In the instant case, Johnson teaches the use of linkers to keep VL2 from binding to VH1 and to keep VL1 from binding to VH2. The desired effect is the binding/association between the domains that recognize the same antigen; VL2 with VH2 and VL1 with VH1.
The person of ordinary skill in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. The skilled artisan will either make those mutations taught by Brinkmann and Carter in the VH1/VL1 pair OR in the VH2/VL1 pair.
4. Applicant’s arguments that the claimed engineered antibodies exhibit unexpected effects in stability and purity when specifically, VL2 and VH2 domains are covalently linked via a disulfide bond formed between cysteine substitutions at the specified positions and associate via oppositely charged residues at the specified positions, are not found persuasive.
Applicant submits that the stability and purity of antibodies #9, #40, #25, #43, #44, #45, #38 and #39 (which have the disulfide bond covalently linking the VL2 and VH2) are superior to antibody #3 (which has the disulfide bond covalently linking the VL1 and VH1 while lacking the disulfide bond covalently linking the VL2 and the VH2).
The Examiner disagrees with this assessment. Antibodies #9, #40, #25, #43, #44, #45 have the disulfide bond covalently linking the VL2 and VH2 AND also have the charged amino acids in VL2 and VH2, while antibody #3 just has the disulfide bond covalently linking the VL1 and VH1.
A fair comparison would be an antibody comprising a disulfide bond covalently linking the VL2 and VH2 (while lacking the disulfide bond covalently linking the VL1 and the VH1) matched with an antibody comprising disulfide bond covalently linking the VL1 and VH1 (while lacking the disulfide bond covalently linking the VL2 and the VH2) OR
an antibody comprising a disulfide bond covalently linking the VL2 and VH2 (while lacking the disulfide bond covalently linking the VL1 and the VH1) and charged amino acids in VH2 and VL2 matched with an antibody comprising disulfide bond covalently linking the VL1 and VH1 (while lacking the disulfide bond covalently linking the VL2 and the VH2) and charged amino acids in VH1 and VL1.
The Examiner also notes other modifications made in the VL3 (8th column across) and VH2 (9th column across) of some of the antibodies. It is unclear what effect, if any, these substitutions have on the stability or purity.
Lastly, MPEP teaches: 716.02 Allegations of Unexpected Results [R-01.2024]
Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986)
716.02(b) Burden on Applicant [R-08.2012] I. BURDEN ON APPLICANT TO ESTABLISH RESULTS ARE UNEXPECTED AND SIGNIFICANT. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992).
The scientific reasoning and evidence as a whole indicates that the rejection should be maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ELIZABETH C. KEMMERER/ Primary Examiner, Art Unit 1674
/R.M.D/Examiner, Art Unit 1647 8/4/2025
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