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 .
DETAILED ACTION
Status of the Claims
1. Claims 1-41 are all the original claims filed on 2/20/2023. In the Preliminary Amendment of 2/7/2024, Claims 3, 5, 7-9, 22, 24-26, 37, 39, and 41 are amended. Claims 1-41 are pending.
Priority
2. USAN 18/042,267, filed 02/20/2023, is a National Stage entry of PCT/US2021/046770, International Filing Date: 08/19/2021, PCT/US2021/ 046770 Claims Priority from Provisional Application 63/068,306, filed 08/20/2020.
Information Disclosure Statement
3. As of 10/28/2025, a total of two (2) IDS are filed: 2/7/2024; and 2/7/2024. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Specification
4. The disclosure is objected to because of the following informalities:
a) The use of the term, Sepharose, ATCC, nanobody, DuoBody, KinExa, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
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.
b) The specification at [0012], [0021], [0038], [0060], [0069] and [0086] is objected to for failing to include the sequence identifier (SEQ ID NO) for the peptide sequences > 4 amino acids in length as pursuant to 37 CFR 1.821-1.825.
Appropriate correction is required.
Claim Objections
5. Claims 1-41 are objected to because of the following informalities:
a) Claims 1-41 recite the terms substituting, modifying, deleting, and mutation. In some instances, a mutation seemingly encompasses a substitution, while it is not clear what a modification encompasses.
b) Amend claim 19 to recite “i) the first VH-CH1 polypeptide comprises a F126C mutation and a C220A mutation; and ii) the first VL-CL polypeptide comprises a E123C mutation and a C214A mutation.”
c) Amend claim 36 to recite “i) the first VH-CH1 polypeptide comprises a F126C mutation and a C220A mutation; and ii) the first VL-CL polypeptide comprises a E123C mutation and a C214A mutation.”
Appropriate correction is required.
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.
Written Description
6. Claims 1-41 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.
Claim interpretation
The object of the invention is to generate “a new placement for a non-canonical disulfide bond and as such the generation of an asymmetric cysteine interface between two Fabs present in the same molecule which will further enable the production of multispecifics (abstract).
Claims 1-17 recite “substituting, modifying or deleting” in generic claim 1 for VH-CH1 and VL-CL followed by “mutation” in the dependent claims. The dependent claims recite “introducing” a mutation.
Claims 18-34 recite “lacking a cysteine” in Claim 18. The dependent claims recite mutations.
Claims 35-41 recite “lacking a cysteine” in Claim 18. The dependent claims recite mutations.
“modify”/ “modifying”: the specification does not provide a, per se, definition for the claimed term.
The specification uses mutation and modification interchangeably in the knob-to-holes changes in heavy chains:
[0254] In some instances, antibodies of the disclosure have immunoglobulin chains in which the heavy chains have been modified by mutating selected amino acids that interact at the interface between two polypeptides so as to preferentially form a multispecific antibody.
The specification teaches variants of the antigen binding proteins that comprise substitutions, deletions and insertions
[0279] Such variants include, for example, deletions and/or insertions and/or substitutions of residues within the amino acid sequences of the antigen binding proteins. Any combination of deletion, insertion, and substitution is made to arrive at the final construct, provided that the final construct possesses the desired characteristics.
The specification teaches modifications include glycosylation and phosphorylation
[0279] The amino acid changes also may alter post-translational processes of the antigen binding protein, such as changing the number or position of glycosylation sites. In certain embodiments, antigen binding protein variants are prepared with the intent to modify those amino acid residues which are directly involved in epitope binding.
“mutation”: the specification seemingly equates a mutation with a substitution
[0273] In other embodiments, glycosylation of the multispecific antigen binding proteins described herein is decreased or eliminated by removing one or more glycosylation sites, e.g., from the Fc region of the binding protein. Amino acid substitutions that eliminate or alter N-linked glycosylation sites can reduce or eliminate N-linked glycosylation of the antigen binding protein. In certain embodiments, the multispecific antigen binding proteins described herein comprise a mutation at position N297 (EU numbering), such as N297Q, N297A, or N297G.
The POSA cannot reasonably ascertain what the full breadth and scope of the claimed method encompasses without sufficient guidance provided in the original filed specification as to the changes that are made de minimus to residues (i.e., 220 (VH-CH), and 214 (VL-CL)). The POSA cannot ascertain whether “modifying” is meant to encompass an amino acid change that includes but not limited to insertions, deletions, substitutions, glycosylation, phosphorylation, mutations, etc., or combinations thereof.
Because applicant seeks patent protection for all such antigen binding proteins, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Scope of the claimed genus
Claims 1-41 recite the terms substituting, modifying, deleting, and mutation. In some instances, a mutation seemingly encompasses a substitution, while it is not clear what a modification encompasses. Generic claims 1, 18 and 35 are not limited to whether the amino acid residues are natural, non-natural, synthetic, mimetic, etc. Dependent claims that recite specific residue changes refer to those changes as mutations that which otherwise resemble substitutions.
Summary of species disclosed in the specification
Applicant’s specification fully discloses in two pages dedicated to two (2) examples of non-canonical residues in the CH1/CL interface that permit replacement of canonical disulfide bonds. The residue changes constitute
[0183] In order to mimic natural expression levels, purification profile and overall stability of an antibody, an extensive screening of CH1/CL interface was performed. Two residues with optimal rotamer configuration of their side-chains and distance between respective Cα-Cα of around 4.5 Å was sought. The results show that F126C in HC and E123C in the LC can successfully replace the canonical disulfide bound and it can be efficiently deployed together with CPMv1 (HC-S183K and LC-S176E) (FIG. 2).
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Claims 20-21 and 23 are rejected because they depend from Claim 18.
Are the disclosed species representative of the claimed genus?
It is asserted that the disclosed species are not representative of the claimed genus because the claims encompass any amino acid variation at residues 220 (VH-CH) and 214 (VL-CL)). The claims recite modifications and mutations where there is inconsistency or lack of clarity in the meaning of the terms in the original filed specification. Dependent claims 8, 10-17 and 24-34 recite differently structured antigen binding formats where these permutations are not tested by SEC and MCE analytics after the ProA purifications step to evaluate aggregates and low molecular weight species. Dependent claims 8, 10-17 and 24-34 recite differently structured antigen binding formats where these permutations are not tested for cell expression compared to controls.
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has not provided a common structure sufficient to visualize the genus of all possible functional variants. Applicants’ admission of record is at
[0188] The results show that V2232 and V2233 have generated comparable multispecific yields to those using V503 and V603 controls. Interestingly, the data shows that V2233 when swapped display a higher percent recover than the best control (40% vs 35%, respectively). Moreover, engineered F126C and E123C do not appear to negatively impact the capability of the cell in express these multispecific molecules. The formation of the correct cysteine bound between these two inserted cysteines was first assess by the elution in low pH after ProA purification step and further confirmed by MSQC.
Even in 2021, antibodies are still not understood well enough to allow researchers to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” Vajda et al., “Progress toward improved understanding of antibody maturation,” Current Opinion in Structural Biology, 67 pp. 226-231 (2021 (PTO 892)) at p. 226, col. 2, lines 20-24.
As recently as 2020, researchers were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus for reliably assigning different antibody structures based on sequence data for two clones, V2232 and V2233, which would support the premise that the inventors possessed the full scope of the claimed invention.
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.
7. Claim(s) 1-41 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al (US 11130808) in view of Brinkmann et al (MABS 2017, VOL. 9, NO. 2, 182–212) and Hsu et al (WO 2017/106383 (IDS 2/7/2024)).
Yan in view of Brinkmann teach antigen-binding molecules modified at the CH1-CL interface rending the invention prima facie obvious.
AS regards claims 1-41: Yan teaches multispecific (bispecific or “at least one Fab region” (Claim 35)) and rearranged multispecific (bispecific) antibodies (Figures 2, 3, 15) that in view of Brinkmann (Fig. 1-3) encompass different formats.
AS regards claims 1-2, 18-19 and 35-36, Yan teaches the first antibody is a human and/or humanized lgG1 antibody, the cysteine at position 220 in the HC1 is substituted with another amino acid, and the cysteine at position 214 in the LC1 is substituted with another amino acid, where the first antibody is an lgG1 antibody, and it comprises the alterations C220G/A in the HC1 and C214S/A/G in the LC1.
AS regards claims 1-2, 18-19 and 35-36, Yan teaches the CH1 and CL domains comprise a pair of contacting cysteine residues, wherein one cysteine of the pair is in the CH1 domain and the other is in the CL domain, and wherein the CH1 and CL positions, respectively, of the pair of cysteines are selected from the group consisting of:
126 and 124; and 126 and 121. Yan teaches antibodies with the HC alteration F126C. Yan teaches the LC alteration Q124C. Yan teaches that CH1 amino-acid 126 contacts CL-kappa amino-acids 121, 123 and 124:
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Accordingly, the POSA would reasonably contemplate substituting residue CL 123 since the residue inherently contacts residue CH1 126.
AS regards claims 14-17 and 31-34, Yan teaches Fc region knobs-in-holes (“HC- and LC-partner-directing alterations can be substitutions or pre-existing amino acids that create a knob and a hole (or a protuberance and a cavity) at contacting residues”; “Examples of alterations (including in some cases amino acids present in the original sequence) that disfavor the formation of heterodimers include, without limitation, the following: 409D/E plus 399R/K in one HC where the other HC has an arginine at position 409 (e.g., as in a human IgG4 antibody); 409D/E, 399R/K, plus 392D/L/Y/M/W/I/V/F in one HC where the other HC has an arginine at position 409; 392E/D plus 399R/K in one HC and 392K/R plus 399D/E other HC; 399K/R, 409D/E, plus 392D/E in one HC and 399D/E, 409K/R, plus 392K/R in the other HC; 399K/R, 409D/E, 356K/R, plus 392D/E in one HC and 399D/E, 409K/R, 356D/E, plus 392K/R in the other HC; 399K/R, 409D/E, 357K/R, plus 392D/E in one HC and 399D/E, 409K/R, 357D/E, plus 392K/R in the other HC; 399K/R, 409D/E, 356K/R, plus 438D/E in one HC and 399D/E, 409K/R, 356D/E, plus 438K/R in the other HC; 399K/R, 409D/E, 357K/R, plus 370D/E in one HC and 399D/E, 409K/R, 357D/E, plus 370K/R in the other HC; 399K/R, 409D/E, 356K/R, 392D/E, 357K/R, plus 370D/E in one HC and 399D/E, 409K/R, 356D/E, 392K/R, 357D/E, plus 370K/R in the other HC; 399K/R, 409D/E, 356K/R, 392D/E, 357K/R, plus 439D/E in one HC and 399D/E, 409K/R, 356D/E, 392K/R, 357D/E, plus 439K/R in the other HC; 366Y/W plus 407T/A in one HC and 366T/A plus 407Y/W in the other HC; 405A/T plus 394W/Y in one HC and 405W/Y plus 394A/T in the other HC; 407Y/W in one HC and 366Y/W in the other HC; 366Y/W, 407T/A, plus 405A/T, 394W/Y in one HC and 366T/A, 407Y/W, plus 405Y/W, plus 394A/T in the other; and 366W/Y, 368A/T, plus 407V/T/A in one HC and 366T/A/S, 368L, plus 407Y/W in the other HC.”;
AS regards claims 9, 26 and 41, Yan teaches peptide linkers (Figure 1 showing a linker between the VH-CH1 and the VL-CL) that in view of Brinkmann encompass glycine-serine-rich linkers (p. 185, col. 1) such as a flexible GGGGSG linker, a G4S linker, and GGGGSGGGS linkers.
AS regards claims 3-6, 20-23, and 37-40, Yan teaches that CH1 amino-acid 183 contacts CL-kappa amino-acid 176:
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. The residue substitutions 183K/E and 176E/K confer electrostatic steering in the CH1-CL interface which Yan appreciates for the Fab B of Antibody 3 in panel B of Fig 3 in Yan. Still further and in view of Hsu, the subsequent 183/176 modifications to the invention are taught as
a. the first CH1 domain comprises a S I83E mutation using EU numbering; b. the second CH1 domain comprises a. S 183K mutation using EU numbering;
235 c. the first CL domain comprises a S 176K mutation using EU numbering; and
d. the second CL domain comprises a S 176E mutation using EU numbering.
The ability to generate a single antibody -based construct that can recognize multiple targets simultaneously, is paramount to advance many therapeutics candidates to clinic. Often, this implies extensive protein design with vary degrees of success. In the case of multispecific antibodies, the driving of the HC/LC pairing in the Fab region represents one of the most difficult challenges yet in the field of multispecific engineering. The reference combinations provide a non-canonical disulfide bond that confers the generation of an asymmetric cysteine interface between two Fabs present in the same molecule which will further enable the production of multispecifics. The inclusion of other CH1-CL interface residue substitutions that confer electrostatic steering in the CH1-CL interface add to the formation of a stable but diverse multispecific construct.
Conclusion
8. No claims are allowed.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643