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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10 February 2026 has been entered.
Status of Application, Amendments and/or Claims
The amendment and Applicant’s arguments, filed 10 February 2026, have been entered in full. Claims 1-14, 16, 17, 24-28, 30 and 31 are canceled. Claim 15 is amended. New claims 32-40 are added. The Zhou Declaration under 37 CFR 1.132, filed 10 February 2026, has been entered in full. Claims 15, 18-23, 29, 32-40 are under examination.
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.
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, 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 the Examiner's Rejection relies on a Mischaracterization of Johnson et al.
Applicant argue that the Office Action alleges that "the engineered antibody taught by Johnson comprises scFv and scFab," (see, Office Action page 8, para. 2; page 13, para. 3) and relies on this characterization to establish a motivation to modify Johnson with the teachings of Brinkmann (disclosing disulfide bonds in single chain Fabs or single chain Fv fragments) and Carter (disclosing charge mutations in Fab domains).
Applicant argues that the engineered antibody taught by Johnson does not comprise scFv (i.e. single chain) or scFab (i.e. single chain). Applicant argues that Johnson discloses a TRIDENT format comprising a diabody (i.e. di-chain) in combination with a Fab domain (i.e. di-chain), which are fundamentally different from the single-chain fragments. Applicant argues that Johnson clearly distinguished "Diabody-Type Binding Domain" from "Fab-Type Binding Domain" and an "scFv-Type Binding Domain". Applicant directs the Examiner’s attention to paragraph [0181].
Applicant submits that there is no motivation to modify the Diabody portion of Johnson's molecule with the mutations disclosed in scFv or Fab.
Applicant’s arguments have been fully considered but are not found persuasive for the following reasons.
1. As was stated in the original rejection (specifically at pages 9-13 of Office Action dated November 29, 2024). Johnson et al. teach an engineered antibody that is the same as that described in instant claim 15 (see Johnson at Figure 6A for example), except for cysteine substitutions made in the VL2 and VH2 to form a disulfide bond and charged substitutions made at position 44 (or position 38) of VL2 and position 103 (or position 39) of VH2. In addition, Johnson et al. teach peptide linkers between VL2 and VH1 and peptide linkers between VL1 and VH2. (see Figure 6A and para 0162-0163, for example).
2. In response to Applicant’s arguments that the engineered antibody taught by Johnson does not comprise scFv (i.e. single chain) or scFab (i.e. single chain) and relies on this characterization to establish a motivation to modify Johnson with the teachings of Brinkmann (disclosing disulfide bonds) and Carter (disclosing charge mutations in Fab).
The Examiner submits that the engineered antibody of Johnson comprises heavy chain variable (VH1 and VH2) domains and light chain variable (VL1 and VL2) domains.
Brinkmann et al. teach wherein a bispecific antibody is trivalent or tetravalent. Brinkman et al. teaches cysteine substitutions mutations made in a heavy chain variable domain (VH) and in a light chain variable (VL) to form disulfide bonds. Brinkmann et al. teach in one embodiment the disulfide bond between the variable domains of the single chain Fab fragments comprised in the antibody according to the invention is between heavy chain variable domain (VH) at position 44 (or position 105) and light chain variable domain (VL) at position 100 (or position 43) (numbering always according to EU index of Kabat).
Brinkmann et al. clearly teach that these mutations enable the formation of stable interchain disulfides between VH and VL, which in turn stabilizes the resulting disulfide-stabilization. This provides the motivation to add these types of mutations to the VH domain and the VL domain of the engineered antibody of Johnson et al.
APPLICANT’S ARGUMENT TWO: Applicant argues that there is a lack of motivation to modify the antibody of Johnson with Carter and a lack of reasonable expectation of success.
Applicant argues that the Examiner's proposed combination is based on impermissible hindsight. Applicant argues that Carter discloses the introduction of charged residue substitutions in the context of Fab fragments, where such substitutions are used to stabilize or control pairing at Fab-specific interfaces. Applicant argues that Carter is directed to Fab domain and does not disclose or suggest applying charged framework substitutions to Diabody domains, which differ structurally and assemble through a distinct non-covalent Fv-Fv association.
Applicant argues that Johnson, in contrast, discloses a Diabody-Fab format in which Diabody heterodimerization is achieved through tandemly repeated charged E-coil and K-coil domains (Johnson, paragraph [165]). Applicant argues that Johnson already provides a specific and complete mechanism for promoting correct Diabody chain association. Applicant argues that Carter neither identifies any deficiency in such an approach nor suggests that additional charged residue substitutions within the Diabody variable domains would be desirable or necessary.
Applicant submits that one of ordinary skill in the art would have lacked motivation to apply Carter's Fab-specific charged residue substitutions to the Diabody portion of Johnson, particularly where Johnson already addresses Diabody heterodimerization using a different structural strategy. Applicant argues that Carter provides no teaching or reasonable expectation of success that charged residue substitutions designed for Fab interfaces could be applied to the structurally distinct Diabody interface without adversely affecting Diabody folding or assembly.
Applicant’s arguments have been fully considered but are not found persuasive for the following reasons.
1. In response to Applicant’s argument that Carter is directed to Fab domains and does not disclose or suggest applying charged framework substitutions to Diabody domains, which differ structurally and assemble through a distinct non- covalent Fv-Fv association.
As was stated above, the engineered antibody of Johnson et al. comprises heavy chain variable (VH1 and VH2) domains and light chain variable (VL1 and VL2) domains. The engineered antibody of Johnson et al. comprises CH3 domains.
Carter et al. teach modifications made in the CH3 domain. Carter et al. teach wherein the domain comprises Thr366, Leu368, Tyr407 replacements with Trp/Ser, Ala and Val, respectively. Carter et al. teach in some embodiments according to (or as applied to) any of the embodiments above the VH domain of VH1 and/or VH2 comprises an amino acid substitution at position Q39 (Kabat numbering), and the VL domain of VL1 and/or VL2 comprises an amino acid substitution at position Q38 (Kabat numbering). In some embodiments the amino acid at Q39 in the VH domain is replaced with a positively charged residue, and the amino acid at Q38 in the VL domain is replaced with a negatively charged residue. In some embodiments the amino acid at Q39 in the VH domain is replaced with a negatively charged residue, and the amino acid at Q38 in the VL domain is replaced with a positively charged residue. In some embodiments the positively charged residue is selected from the group consisting of R and K and the negatively charged residue is selected from the group consisting of D and E.
Carter et al. clearly teach Q38 and Q39 mutations result in higher expression, higher production and better assembly. In addition, Thr366, Leu368, Tyr407 replacements with Trp/Ser, Ala and Val, respectively, in the CH3 domain are known in the art to induce heterodimerization. This provides the motivation to add these types of mutations to the VH domain, the VL domain and the CH3 of the engineered antibody of Johnson et al.
2. In response to Applicants argument that one of ordinary skill in the art would have lacked motivation to apply Carter's Fab-specific charged residue substitutions to the Diabody portion of Johnson, particularly because Johnson already addresses Diabody heterodimerization using a different structural strategy.
MPEP 2144 IV teaches: The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Linter, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972).
In the instant case, using the amino acid residue substitutions taught by Brinkmann and Carter, would provide increased/additive stabilization of the heterodimerization or provide an alternative strategy for heterodimerization.
3. Regarding Applicant’s arguments that Carter provides no teaching or reasonable expectation of success that charged residue substitutions designed for Fab interfaces could be applied to the structurally distinct Diabody interface without adversely affecting Diabody folding or assembly.
The Examiner submits that Carter teaches mutations made in the VL, VH and CH3 according to Kabat numbering. One skilled in the art could employ the teachings to add these types of mutations in the engineered antibody of Johnson et al. with a reasonable expectation of success. Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O' Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
4. Regarding Applicant’s arguments that the Inventors demonstrated that introducing charged residues alone within the Diabody failed to stabilize the Diabody (paragraph [345] of the instant specification) and combining charged residues with standard "knob-in-hole" mutations failed to stabilize the diabody heterodimer, which shows there is no reasonable expectation of success introducing charged mutations on diabody.
The Examiner submits that Carter et al. teach combining substituted charged residues at position 44 (or position 38) of VL2 and position 103 (or position 39) of VH2 with Thr366, Leu368, Tyr407 replacements with Trp/Ser, Ala and Val, respectively, in the CH3 domain. The Examiner does not see a teaching of these mutations and the failure to stabilize the diabody heterodimer in paragraph 345 of the instant specification.
APPLICANT’S ARGUMENT THREE: Applicant argues that there is evidence of unpredictability and unexpected results. Applicant argues that the Inventors of the present application made over 50 engineered antibody constructs.
Applicant argues that by testing such a vast range of antibodies produced from each construct, the Applicant demonstrated that:
1) if both VL1-VH1 and VL2-VH2 pairs on the diabody arm are covalently linked via disulfide bonds, the engineered antibody forms large aggregates and the yield of the desired engineered antibody decreases (e.g., Paragraphs [0107] and [0346]);
2) when a combination of cysteine and charge substitutions are introduced into the claimed positions in only one VH and VL pair, in particular, the VH2 and VL2 pair, the obtained antibodies consistently showed high purity and high stability of over 95%, and in some cases, over 99%.
Applicant argues that this discovery is surprising. Applicant submits that despite the numerous substitutions known in the art to stabilize VH and VL domains, the Applicant found that many substitutions failed to effectively stabilize the Diabody-Fab structure or prevent mispairing, whether used alone or in combination. Applicant directs the Examiner’s attention to the instant application para 345; Tables 5-11 (which showed constructs #3, #7, and #11 only achieved a purity ranging from 60% to 87%) and Item 14 of Dr. Zhou Declaration.
Applicant argues that neither Johnson nor Brinkmann or Carter, either alone or in combination, would not render the amended claims obvious. Applicant argues that although Johnson disclosed a similar antibody design containing trivalent binding molecules which includes a diabody arm and a Fab arm, Johnson employed a completely different strategy to associate the two polypeptides within the diabody arm, (i.e., through coil-coil fragments outside the VH and VL domains). Applicant maintains that in view of Johnson's linkage technology, a person of ordinary skilled in the art would not be motivated to introduce specifically the claimed cysteine substitutions and oppositely charged amino acid substitutions between the interface of one VH- VL pair and avoid introducing a disulfide bond between the other VH-VL pair..
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), or a single-chain Fab (scFab), that binds to a second antigen, where cysteine residues are introduced into the only VH and VL pair within the scFv or scFab. Applicant argues in both designs by Brinkmann, there is one only pair of VH and VL domains.
Applicant argues that Carter discloses a multi-specific antibody comprising a classic antibody structure with VH, CH1, VL and CL, i.e., a Fab as an antigen binding domain, where oppositely charged residues are introduced into the only VH and VL pair within the Fab. Applicant argues that Brinkmann nor Carter teaches the impact of possible interaction between the second VH and VL pairs within the diabody arm of the present invention as each only includes a single pair of VH and VL domains in their scFv or Fab based constructs. Applicant maintains that Johnson, in combination with Brinkmann and Carter fails to teach the lack of a second disulfide bond and its negative impact on an engineered antibody having multiple binding domains.
Applicant’s arguments have been fully considered but are not found persuasive for the following reasons.
1. The Examiner has already addressed why a person of skill in the art would have been motivated to modify the engineered antibody of Johnson, in spite of Johnson’s teaching of heterodimerization using a different structural strategy.
2. The Examiner has already addressed the arguments regarding the structural differences of the engineered antibody of Johnson and that of Brinkmann and Carter and why one skilled in the art would use the teachings of Brinkmann and Carter to make substitutions in the engineered antibody of Johnson.
3. Regarding Applicant’s argument that if both VL1-VH1 and VL2-VH2 pairs on the diabody arm are covalently linked via disulfide bonds, the engineered antibody forms large aggregates (polymers) and the yield of the desired engineered antibody decreases (e.g., Paragraphs [0107] and [0346])).
The Examiner notes that instant claim 32 encompasses an engineered antibody wherein both VL1-VH1 and VL2-VH2 pairs on the diabody arm are covalently linked via disulfide bonds. That is to say, instant claim 15 recites, “wherein the VL1 and VH1 domains are not covalently linked via a disulfide bond” but claim 32 does not recite any explicit limitations regarding VL1 and VH1 domain linkage.
Thus, Applicant’s arguments are contradictory, in light of new claim 32.
4. Regarding Applicant’s arguments that when a combination of cysteine and opposite charge substitutions are introduced into the claimed positions in only one VH and VL pair, in particular, the VH2 and VL2 pair, the obtained antibodies consistently showed high purity and high stability of over 95%, and in some cases, over 99% and that this discovery is surprising.
The Examiner submits that this is not surprising because Brinkmann and Carter already teach these mutations. Brinkmann et al. teach the same cysteine substitutions made in the VH and VL domain, as currently recited and that states that the mutations enable the formation of stable interchain disulfides between VH and VL, which in turn stabilizes the resulting disulfide-stabilization. Carter et al. teach the same charge amino acid substitutions made in the VL/VH domain and the same mutations made in the CH3 domain, as currently recited. Carter et al. teach that the mutations induce stable dimerization, higher expression and higher production.
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 would make those mutations taught by Brinkmann and Carter in the VH1/VL1 pair OR in the VH2/VL1 pair of the engineered antibody of Johnson.
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.
5. Regarding Applicant’s arguments directed to the engineered antibodies constructs made in the instant specification, the surprisingly associated properties and evidence of unpredictability and unexpected results.
The Examiner submits that Applicant’s arguments regarding the surprisingly associated properties and evidence of unpredictability and unexpected results of the engineered antibody are not found persuasive because of the teachings of Johnson, Brinkmann and Carter.
In addition, the arguments are not commensurate in scope with the claims, as currently recited. Table 3 from the instant specification lists the engineered antibodies. The engineered antibodies argued by Applicant have specific mutations in the VL domain, specific mutations in the VH domain and specific linkers. The Examiner submits that none of the instant claims recite engineered antibodies with these specific mutations and linkers.
APPLICANT’S ARGUMENT FOUR and the Declaration II of Zhou under 37 CFR 1.132. Applicant argues unexpected results in effectively minimizing mispairing in Diabody-Fab Formats. Applicant maintains that the claimed invention also addresses and solves a significant technical challenge inherent to asymmetric multi-specific antibody formats: light chain mispairing. Applicant argues that that according to the Zhou Declaration, it is well understood in the art that light chain mispairing presents a significant technical hurdle in the development and manufacturing of asymmetric multi-specific antibodies. Applicant argues that minimizing mispaired byproducts is essential for both the therapeutic success and manufacturing viability of asymmetric bispecific antibodies.
Applicant argues that the Inventors have demonstrated that the claimed engineered Diabody-Fab antibody format achieves unexpectedly low light chain mispairing. Applicant directs the Examiner’s attention to instant application at Table 18. Applicant states that the SDS-PAGE analysis of trispecific antibodies #50 and #54 demonstrates no visible light chain mispairing side products, and the SEC purified samples showed a purity of over 99%. Applicant directs the Examiner’s attention to Item 8 of the Declaration. Applicant argues that the Declaration further provides characterization data using Liquid Chromatography-Mass Spectrometry (LC-MS) to analyze a specific molecule of the claimed format. Applicant argues that the results confirmed non-detectable levels of light chain mispairing products, validating the high purity observed via SDS-PAGE and confirming the claimed engineered VH2/VL2 interface effectively prevents the formation of mispaired byproducts. Applicant directs the Examiner’s attention to Items 9-14 of the Declaration.
Applicant submits that the unexpected result is further highlighted by a publication showing comparative LC-MS study conducted on the DuetmAb format developed by MedImmune, which, despite of engineered interface, still gives rise to mispairing side products. Applicant submits that in direct contrast, the claimed engineered antibody showed almost no light chain mispairing side products under identical analytical conditions.
The Zhou Declaration II under 37 CFR 1.132: The Declaration states that to
evaluate the efficacy of the claimed invention, we expressed Antibody #50 and Antibody #54 as disclosed in the application. LC1 and HC1 are connected via a disulfide bond between VL2 (C100) and VH2 (C44) and oppositely charged residues between VL2 (K38) and VH2 (D39), while LC2 and HC2 are linked through a disulfide bond between CL (C214) and CH1 (C233). This format is also called "TRIAD". The Declaration states that as shown in the Example 7 of the instant Application, Antibody #50 and Antibody #54 were purified by protein A binding, and then subject SDS-PAGE analysis. The Declaration states that the SDS-PAGE image shows that Antibody #54 migrated as a single, distinct band at approximately 150 kD, which corresponds to the molecular weight of the correctly paired, fully assembled product and that similar results was observed for Antibody #50. The Declaration states that there is no significant band at 125 kD or 100kD, indicating absence of species resulting from light chain mispairing. The Declaration states that the purities of antibody # 50 and antibody # 54 were shown to be 99.14 and 99.24%, respectively.
The Declaration teach analyzing a TRIAD molecule Antibody X, which consists of two distinct light chains (LCI and LC2) and two distinct heavy chains (HCI and HC2). Disulfide bonds form between LC1 C99 (VL2, Kabat: 100C) and HC1 C160 (VH2, Kabat: 44C), and between LC2 C214 (CL, Kabat: 214C) and HC2 C224 (CH1, Kabat: 233C), establishing correct light chain pairing. The Declaration states that when using LC-MS, none of these impurities were detected at their expected mass positions. The mass spectra display dominant peaks corresponding to the calculated mass of the correctly assembled antibodies, without obvious signals attributable to mispaired byproducts. The Declaration states that this confirms that the TRIAD structure prevents mispairing between LC1 and HC2 or between LC2 and HC1, and solves the long-felt problem of light chain mispairing. The Declaration states that in addition to LC-MS, disulfide peptide mapping analysis for light chain mispairing was conducted. . Mispaired LC1 and LC2 light chains could theoretically generate disulfide- scrambled peptides with non-native interchain linkages between HC1-LC2 and HC2-LC1.
The Declaration concludes by stating that the fact that TRAID format successfully prevents light chain mispairing is unexpected and impressive. The Declaration states that despite extensive engineering and the development of multiple multispecific antibody formats aimed at minimizing light-chain mispairing, mispaired species continue to be observed. The Declaration states that the DuetMab platform, developed by MedImmune, combined knobs-into-holes Fc mutations with the introduction of an engineered disulfide at the CH1-CL interface to promote correct chain associations. The Declaration argues that Wang et al. reported that, when the protein A-purified samples were tested by LC- MS analysis, three chromatographic peaks were detected. Intact mass measurement of the main peak indicated coelution of two species: the correctly paired bispecific antibody product and a mispaired species with dual kappa light chains.
Applicant’s arguments have been fully considered but are not found persuasive. The Zhou Declaration under 37 CFR 1.132, filed 10 February 2026, is insufficient to overcome the rejection of claims 15, 18-23, 29 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) as set forth in the last Office action AND the New rejection of claims 15, 32-40 under 35 U.S.C. 103 as being unpatentable over Bonvini et al. (US 2017/0204176; published July 20, 2017, priority date May 29, 2014) in view of Brinkmann et al. (Reference of record; US 2010/0081 796; published April 1, 2010) and Carter et al. (Reference of record; US 2018/0177873; published June 28, 2018, priority date April 24, 2015).
This is because the showing is not commensurate in scope with the claims. That is to say, TRIAD Antibody #50 and Antibody #54 and the purported associated unexpected results discussed by Applicant and the Declaration do not match the instant claims as currently recited.
TRIAD Antibody # 50 and TRIAD Antibody # 54 each recite a specific domain order, recite specific substitution mutations made in the VL domain, recite specific substitution mutations made in the VH domain, recite specific substitutions mutations made in the CH3 domain, recite specific linkers and recite the antigens that the antibody binds (i.e. CD19 and CD3).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
NEW CLAIM REJECTIONS/OBJECTIONS
Claim Rejections-35 USC § 112(a) or 35 U.S.C. 112 (pre-AIA ), First paragraph, Written description, New Matter
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 15, 18-23, 29 (and dependent new claims 33-36 and 40) 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 New Matter Rejection.
The specification as originally filed does not provide support for the invention as now claimed:
“..wherein the VL1 and VH1 domains are not covalently linked via a disulfide bond" (see claim 15).
Applicant's amendment, filed 10 February 2026, asserts that no new matter has been added and directs support to paragraphs [0107] and [0346]. Applicant argues that the specification demonstrates that if both VL1-VH1 and VL2-VH2 pairs on the diabody arm are covalently liked via disulfide bonds, the yield of the engineered antibody decreases.
Applicant’s arguments have been fully considered but are not found persuasive.
The specification teaches the following:
[0107] In some embodiments, there are both VL1-VH1 and VL2-VH2, purity of product will increase but yield will decrease, thus may not be preferred.
[0346] With disulfide bonds introduced to the interface of one VL-VH pair, further introduction of disulfide bonds to the interface of the second pair of VL-VH resulted in large quantities of polymers in the product, regardless of other modifications made to the second VL-VH pair. With disulfide bonds and paired charged residues introduced to the interface of one VL-VH pair, further introduction of paired charged residues to the interface of the second pair of VL-VH improved purity of the product while caused certain decrease in expression level of the product.
The Examiner cannot find a teaching of “wherein VL1 and VH1 domains are not covalently linked via a disulfide bond”. The wording or connotation of the instant claim is not apparent from said sections.
The instant claims now recite limitations which were not disclosed in the specification as filed, and now change the scope of the instant disclosure as-filed.
Applicant is required to cancel the new matter in the response to this Office action. Alternatively, Applicant is invited to provide specific written support for the “limitations” indicated above or rely upon the limitations set forth in the specification as filed.
NEW 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.
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, 32-40 are rejected under 35 U.S.C. 103 as being unpatentable over Bonvini et al. (US 2017/0204176; published July 20, 2017, priority date May 29, 2014) in view of Brinkmann et al. (Reference of record; US 2010/0081 796; published April 1, 2010) and Carter et al. (Reference of record; US 2018/0177873; published June 28, 2018, priority date April 24, 2015).
Bonvini et al. teach that the present invention relates to Tri-Specific Binding Molecules, which are multi-chain polypeptide molecules that possess three Binding Domains and are thus capable of mediating coordinated binding to three epitopes (abstract). Bonvini et al. teach the tri-Specific Binding Molecule is preferably characterized in possessing binding domains that permit it to immunospecifically bind to: (1) an epitope of a first Cancer Antigen, (2) an epitope of a second Cancer Antigen, and (3) an epitope of a molecule that is expressed on the surface of an immune system effector cell, and are thus capable of localizing an immune system effector cell to a cell that expresses a Cancer Antigen, so as to thereby facilitate the killing of such cancer cell (para 0004).
Bonvini et al. teach an engineered antibody comprising 4 polypeptides as recited in instant claims 15 and 32 (Figures 4A, 4B, for example)(applies to claims 15 and 32). Bonvini et al. teach linkers between VL2 and VH1 and linkers between VL1 and VH2. Bonvini et al. teach that the linkers are 5-9 amino acids in length (Figure 4 and para 0441)(applies to claims 39 and 40). Bonvini et al. teach wherein the molecule targets tumor antigens (para 0004)(applies to claims 34, 35 and 38). Bonvini et al. teach wherein the tri-Specific Binding Molecules bind antigens selected from the group consisting of: CD2, CD3, CD16, CD19, CD20, CD22, CD32B, CD64, the B cell Receptor (BCR), the T cell Receptor (TCR), and the NKG2D Receptor (paras 0043-0051)(applies to claims 33, 36 and 37).
Bonvini et al. do not teach making cysteine substitutions at position 100 (or at position 43) in VL2 and position 44 (at position 105) of VH2 wherein VL2 and VH2 are covalently linked via a disulfide bond.
Bonvini et al. do not teach wherein VL2 and VH2 are associated via electrostatic interaction between VL2 with charged substitutions at position 44 (or position 38) and VH2 with at charge substitutions at position 103 (or at position 39).
Brinkmann et al. teach bispecific antibodies (abstract). Brinkmann et al. teach in another embodiment, the bispecific antibody is trivalent or tetravalent (paras 0199-0222). Brinkmann et al. teach in one embodiment the optional disulfide bond between the variable domains of the single chain Fab fragments comprised in the antibody according to the invention is between heavy chain variable domain position 44 and light chain variable domain position 100. In one embodiment the optional disulfide bond between the variable domains of the single chain Fab fragments comprised in the antibody according to the invention is between heavy chain variable domain position 105 and light chain variable domain position 43 (numbering always according to EU index of Kabat) (paras 0229, 0251 and 0255)(applies to claims 15 and 32). Brinkmann et al. teach cysteine residues were introduced at positions in the VH (including Kabat position 44) and VL (including Kabat position 100) domains of the single chain Fab (paras 0319 and 0326). Brinkmann et al. teach that these mutations enable the formation of stable interchain disulfides between VH and VL, which in turn stabilize the resulting disulfide-stabilization (para 0342).
Carter et al. teach multispecific antigen binding proteins comprising one or more mutations in the VH/VL domains and/or CH1/CL domains (abstract). Carter et al. teach wherein modifications are made in the CH3 domain. Carter et al. teach wherein the domain comprises Thr366, Leu368, Tyr407 replacements with Trp/Ser, Ala and Val, respectively (paras 0034-0035). Carter et al. teach in some embodiments according to (or as applied to) any of the embodiments above the VH domain of H1 and/or H2 comprises an amino acid substitution at position Q39 (Kabat numbering), and the VL domain of L1 and/or L2 comprises an amino acid substitution at position Q38 (Kabat numbering). In some embodiments the amino acid at Q39 in the VH domain is replaced with a positively charged residue, and the amino acid at Q38 in the VL domain is replaced with a negatively charged residue. In some embodiments the amino acid at Q39 in the VH domain is replaced with a negatively charged residue, and the amino acid at Q38 in the VL domain is replaced with a positively charged residue. In some embodiments the positively charged residue is selected from the group consisting of R and K and the negatively charged residue is selected from the group consisting of D and E (paras 0016-0020, 0065, 0332 and 0333) Carter et al. teach Q38 and Q39 mutations result in higher expression, higher production and better assembly (paras 0705, 0707 and 0719)(applies to claims 15 and 32).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify the engineered antibody taught by Bonvini et al., wherein
cysteine substitutions are made at position 100 (or at position 43) in VL2 and position 44 (at position 105) of VH2, wherein VL2 and VH2 are covalently linked via a disulfide bond, as taught by Brinkmann et al. and wherein VL2 and VH2 are associated via electrostatic interaction between VL2 with charged substitutions at position 44 (or position 38) and VH2 with at charge substitutions at position 103 (or at position 39), as taught by Carter et al. One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons. Brinkmann et al. teach that certain amino acid positions of VH and VL that are substituted with cysteine residues enable the formation of stable interchain disulfides between VH and VL, which in turn stabilize the resulting disulfide-stabilization in the multispecific antibody. Carter et al. teach Q38 and Q39 mutations result in higher expression, higher production and better assembly of the multispecific antibody.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 15, 21-23, 29, 32-34, 36-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4,11-15 of copending Application No. 17/596,789 in view of Brinkmann et al. (US 2010/0081 796; published April 1, 2010) and Carter et al. (US 2018/0177873; published June 28, 2018, priority date April 24, 2015).
The claims of copending Application No. 17/596,789 teach An engineered antibody, comprising: (i) a first polypeptide that from N-terminal to C-terminal comprises a second light chain variable domain (VL2) binding a second target and a first heavy chain variable domain (VH1) binding a first target, wherein the VL2 is linked to the VH1 via a linker; (ii) a second polypeptide that from N-terminal to C-terminal comprises a first light chain variable domain (VL1) binding a first target and a second heavy chain variable domain (VH2) binding a second target, and a cysteine-containing hinge domain and a CH2-CH3 domain of IgG, wherein the VL1 is linked to the VH2 via a linker; (iii) a third polypeptide that from N-terminal to C-terminal comprises a third heavy chain variable domain (VH3) binding a third target, CHI domain of IgG, a cysteine- containing hinge domain and a CH2-CH3 domain of IgG, wherein the VH3 is linked to CH1 via a linker; and (iv) a fourth polypeptide that from N-terminal to C-terminal comprises a third light chain variable domain (VL3) binding the third target, a cysteine-containing light chain constant domain (CL), wherein the VL3 is linked to CL via a linker; wherein: VL1 and VH1 associate to form a domain capable of binding the first target; VL2 and VH2 associate to form a domain capable of binding the second target; VL3 and VH3 associate to form a domain capable of binding the third target; wherein the first target is CD3, the second target is CD19 and the third target is CD20; wherein the amino acid sequence of VL1 is as set forth in positions 1 to 109 of SEQ ID NO: 11, the amino acid sequence of VH1 is as set forth in positions 112 to 236 of SEQ ID NO: 10, the amino acid sequence of VL2 is as set forth in positions 1 to 106 of SEQ ID NO: 10, the amino acid sequence of VH2 is as set forth in positions 115-234 of SEQ ID NO: 11, the amino acid sequence of VL3 is as set forth in SEQ ID NO: 8, and the amino acid sequence of VH3 is as set forth in SEQ ID NO: 9; VL2 is covalently linked to VH2 via a disulfide bond; CH1 is covalently linked to CL via a disulfide bond; and the cysteine-containing hinge domains of the second and the third polypeptides are covalently linked via a disulfide bond.
The claims of copending Application No. 17/596,789 further teach wherein the linkers are 5-9 amino acids in length. The claims of copending Application No. 17/596,789 further teach wherein one of the CH3 domain comprises a replacement of Thr366 with Trp, and the other CH3 domain comprises replacements of Thr366, Leu368 and Tyr407 with Ser, Ala and Val, respectively.
The claims of copending Application No. 17/596,789 do not teach wherein said VL2 that is covalently linked to VH2 via a disulfide bond is formed between cysteine substitutions at position 43 and 100 or cysteine substitutions at positions 43 and 105.
The claims of copending Application No. 17/596,789 do not teach wherein said VL2 and VH2 are associated via electrostatic interaction between position 38 of said VL2 and position 39 of said VH2.
Brinkmann et al. teach bispecific antibodies (abstract). Brinkmann et al. teach in another embodiment, the bispecific antibody is trivalent or tetravalent (paras 0199-0222). Brinkmann et al. teach in one embodiment the optional disulfide bond between the variable domains of the single chain Fab fragments comprised in the antibody according to the invention is between heavy chain variable domain position 44 and light chain variable domain position 100. In one embodiment the optional disulfide bond between the variable domains of the single chain Fab fragments comprised in the antibody according to the invention is between heavy chain variable domain position 105 and light chain variable domain position 43 (numbering always according to EU index of Kabat) (paras 0229, 0251 and 0255). Brinkmann et al. teach cysteine residues were introduced at positions in the VH (including Kabat position 44) and VL (including Kabat position 100) domains of the single chain Fab (paras 0319 and 0326). Brinkmann et al. teach that these mutations enable the formation of stable interchain disulfides between VH and VL, which in turn stabilize the resulting disulfide-stabilization (para 0342).
Carter et al. teach multispecific antigen binding proteins comprising one or more mutations in the VH/VL domains and/or CH/CL domains (abstract). Carter et al. teach wherein modifications are made in the CH3 domain. Carter et al. teach wherein the domain comprises Thr3866, Leu368, Tyr407 replacements with Trp/Ser, Ala and Val, respectively (paras 0034-0035). Carter et al. teach in some embodiments according to (or as applied to) any of the embodiments above the VH domain of H1 and/or H2 comprises an amino acid substitution at position Q39 (Kabat numbering), and the VL domain of L1 and/or L2 comprises an amino acid substitution at position Q38 (Kabat numbering). The amino acid at Q39 in the VH domain is replaced with a positively charged residue, and the amino acid at Q38 in the VL domain is replaced with a negatively charged residue. In some embodiments the amino acid at Q39 in the VH domain is replaced with a negatively charged residue, and the amino acid at Q38 in the VL domain is replaced with a positively charged residue. In some embodiments the positively charged residue is selected from the group consisting of R and K and the negatively charged residue is selected from the group consisting of D and E (paras 0016-0020, 0065, 0332 and 0333). Carter et al. teach Q38 and Q39 mutations result in higher expression, higher production and better assembly (paras 0705, 0707 and 0719).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify the engineered antibody wherein said VL2 is covalently linked to VH2 via a disulfide bond, as taught by the claims of copending Application No. 17/596,789, wherein positions 44 and 100 (or positions 43 and 105) are substituted with a cysteine residue, as taught by Brinkmann et al. and wherein positions Q39 and Q38 are substituted with charged amino acids, as taught by Carter et al.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons. The engineered antibody, as taught in the claims of copending Application No. 17/596,789, is a species of the engineered antibody taught in the instant claims. A species renders a genus obvious. In addition, Brinkmann et al. teach positions 44 of VH and 100 of VL are substituted with cysteine residues enabling the formation of stable interchain disulfides between VH and VL, which in turn stabilize the resulting disulfide-stabilization in the multispecific antibody. Carter et al. teach Q38 and Q39 mutations result in higher expression, higher production and better assembly of the multispecific antibody. Based on the teachings, it would be obvious to make the instant invention. This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/R.M.D/Examiner, Art Unit 1647 7/27/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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