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 .
Claims 1-21 are currently pending and under consideration. References to particular teachings of the specification including paragraph numbers are made using this application’s PG-PUB.
Specification
The disclosure is objected to because it contains several embedded hyperlinks and/or other form of browser-executable code. See for example, paragraphs 0023, 0065, and 0070 of this application’s PG-PUB. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Drawings
The drawings filed 11/28/2023 are objected to for recitation of amino acid sequences in the absence of a sequence identifier. See for example Figures 1C, 1D, and 1E. 37 CFR 1.821(c). 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825.
Claim Objections
Claim 2 is objected to because of the following informalities: Claim 2, line 5 recites, “and an Fc fragment comprises a first and a second”. Amending “comprises” to “comprising” would make the claim clearer. Appropriate correction is requested.
Claim 11 is objected to for reciting that the light chains or heavy chains of the variable fragment “may have” sequence identity. Applicant is requested to remove the optional language such that the comparisons to particular sequences are clear.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-21 are rejected under 35 U.S.C. 101 because the claimed invention is not supported by either a credible asserted utility or a well-established utility.
The claims are broadly drawn to a recombinant proteinaceous binding molecule comprising: a) a first binding moiety, capable of binding an antigen, having a first binding site for a first antigen, b) a variable domain of either an antibody light chain or an antibody heavy chain of a second binding site for a second antigen, and c) an Fc fragment comprising a first and a second heavy chain, wherein the variable domain of either the antibody light chain or the antibody heavy chain and the first binding moiety are linked via the Fc fragment.
Thus, the broadest reasonable interpretation of the claim is that the invention is drawn to two separate alternative structures with each structure comprising a variable domain of either an antibody light chain or an antibody heavy chain of a second binding site for a second antigen. Thus, in its broadest sense, refer to “alternative 1” and “alternative 2” structures from Figure 1B below.
PNG
media_image1.png
358
504
media_image1.png
Greyscale
As set forth above, the claims encompass a structure of Alternative 1 or Alternative 2. However, there is no credibly utility or well-established utility to support the use of either structure alone. For example, the specification does not specifically teach a credible use for the structure of alternative 2, alone, with the anti-CD3 variable light chain. The specification teaches [0065] that in order to circumvent some of the limitations of the current immunotherapic strategies, such as the specificity of T cell engaging antibodies, a novel antibody format has been developed, based on the binding of one or two tumor associated antigens simultaneously and the activation of an immune response subsequently. These so called KiHss hemibodies are based on a binding moiety, specific for a tumor-associated target, flexibly linked to a variable domain of an antibody light chain (VL) or to a variable domain of an antibody heavy chain (VH) specific for a receptor molecule, like for example the T cell co receptor CD3. Concurrent binding of two KiHss hemibodies (for example, with diverse specificity) on the cell surface of a single tumor cell enables the formation of, for example, an antiCD3 binding domain from the two subunits VL and VH. This allows the recruitment of T cells towards the target cell, leading to an activation of the immune cells and the killing of double positive tumor cells. Referring back to Figure 1B, it is the “complementation” of the anti-CD3 VH and VL domains that are needed to effectively bind the T-cell on CD3:
PNG
media_image2.png
468
512
media_image2.png
Greyscale
In other words, the claims broadly encompass “single” hemibodies where each hemibody contains only one half (either the VH or VL chain) of an active binding site, making a single piece unable to recruit T cells or trigger cell death on its own. An invention that is "inoperative" (i.e., it does not operate to produce the results claimed by the patent applicant) is not a "useful" invention in the meaning of the patent law. See, e.g., Newman v. Quigg, 877 F.2d 1575, 1581, 11 USPQ2d 1340, 1345 (Fed. Cir. 1989); In re Harwood, 390 F.2d 985, 989, 156 USPQ 673, 676 (CCPA 1968). Thus, applicants should amend the claims to incorporate both hemibody structures.
Claims 1-21 are also rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph. Specifically, because the claimed invention is not supported by either a credible asserted utility or a well-established utility for the reasons set forth above, one skilled in the art clearly would not know how to use the claimed invention.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 6-7, 11-13, 15-16, and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2, as written, is generally narrative and indefinite, failing to conform with current U.S. practice rendering the claim unclear as to what is exactly claimed. For example, the claim recites, “and wherein the CH3 domain of the first heavy chain and the CH3 domain of a second heavy chain meet each other at an interface, which interface comprises an original interface between the CH3 domains wherein the CH3 domain of the first or second heavy chain is altered, that within the original interface of the CH3 domain of one heavy chain that meets the original interface of the CH3 domain of the other heavy chain”. which appears to be a literal translation into English from a foreign document. See also lack of antecedent basis in para 9.
Claim 2 recites the limitation "wherein the second monomer". However, there is insufficient antecedent basis for this limitation in the claim because Claim 2 never recites a second monomer prior to the cited limitation.
Claim 6 contains numerous trademark/trade name such as the following:
Affibody®: Registered trademark of Affibody AB.
· Affilin®: Registered trademark of Navigo Proteins GmbH.
· Affimer®: Registered trademark of Avacta Life Sciences.
· Anticalin®: Registered trademark of Pieris Pharmaceuticals.
· Adnectin™: Trademark of Bristol-Myers Squibb / Adnexus.
· Avimer™: Trademark originally of Avidia / Amgen.
· Alphabody™: Trademark of Complix NV.
· Centyrin™: Trademark of Janssen / Johnson & Johnson.
· DARPin®: Registered trademark of Molecular Partners AG.
· Fynomer®: Trademark originally of Covagen / Janssen.
· Nanofitin®: Trademark of Affilogic.
· Atrimer™: Trademark of Anaphore
Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe binding molecules with antibody-like binding properties and, accordingly, the identification/description is indefinite.
Regarding claims 7 and 13, the items within parenthetical expressions: “(CH3 hole-chain)”, “(CH3 knob-chain)” or (CD3, the T cell receptor (TCR) CD28, CD16, NKG2D, 0x40, 4-1 BB, CD2, CD4, CD5, CD8, CD95, CD32a, CD40, CD89, CD64, NKp30, NKp40, PD1, CTLA4, LFA1” renders the claim indefinite because it is unclear whether the limitations within the expressions are merely exemplary (similar to “such as” language) or are part of the claimed invention. See MPEP § 2173.05(d).
Claims 11-12 recite the limitation "wherein the light chain of the variable fragment of the second binding site fused to the CH3-hole chain” (Claim 11) and "the second binding site fused to the CH3-knob chain” (Claim 12) in reference to Claim 1. However, there is insufficient antecedent basis for this limitation in the claim because Claim 1 does not mention fusions to the either the CH3-hole or CH3-knob chain.
Claims 15-16 are rejected as vague and indefinite for several recitations of the term “optionally” in conjunction with proliferative diseases. First, the specification only appears to contemplate the treatment of certain proliferative diseases. For example, the specification teaches [0125] that a disease to be treated or prevented may be a proliferatory disease. Examples of a proliferative disease include, but are not limited to, hemopoietic malignancies, such as acute and chronic myeloic and lymphatic leukemias, as well as lymphomas, or solid tumors. Thus, if the disease to be treated is not a proliferative disease, it’s unclear what non-proliferative diseases are encompassed by the claim. Secondly, the two recitations of “optionally” in claim 16 creates ambiguity as to whether or not the alternatives are distinctive limitations. See MPEP 2173.05(h) II.
Claim 20 recites the limitation "or the monomer of the heterodimeric recombinant proteinaceous binding molecule" in Claim 1. However, there is insufficient antecedent basis for this limitation in the claim because Claim 1 does not claim a monomer.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-6, 8-9, and 14-21 is/are rejected under 35 U.S.C. 102(a)(1) and/or (a)(2) as being anticipated by Woning et al. (US20190218310, published 7-18-2019, filed 12-22-2017).
The broadest reasonable interpretation (BRI) of claim 1 (part c- discussing CH3 domain amino acid substitutions) and similar language set forth in claim 2 is the well-known technique of “knob-in-hole” frameworks (e.g., Ridgway et al, 1996, applicant’s IDS). Thus, references which anticipate or render obvious the particular amino acid substitutions of dependent claim 7 would also anticipate the generic language as set forth in Claims 1 or 2. Further, due to the indefiniteness of Claim 2 as set forth above, the structure of claim 2 is broadly interpretated as the same as claim 1.
As to claims 1-2, Woning et al. teach [0015] a bispecific antigen binding construct which comprises a binding moiety capable of binding an antigen that is linked to an IgG Fc fragment and a variable domain of an antibody heavy chain that targets a second antigen linked to IgG Fc fragment with knob in hole construction in the CH3 domain of the Fc fragment. See Figure 2C. Woning et al. further teach [0009] that binding molecule modifications include the “knobs-into-holes” (KiH) approach which involves the introduction of a bulky residue into one of the CH3 domains of one of the antibody heavy chains. This bulky residue fits into a complementary “hole” in the other CH3 domain of the paired heavy chain so as to promote correct pairing of heavy chains. For example, Figure 3 and [0044] depicts a conventional Fab portion containing CH3-“hole” mutations (T366S/L368A/Y407V) and VHH portion containing a CH3 knob (T366W) mutation. Woning et al. further teach [0102] that the two Fc domains of the antigen binding construct are heterodimerized through hydrophobic interaction effects. This dimerization technique utilizes hydrophobic interactions instead of electrostatic ones to promote and strengthen Fc domain pairing in the CH3/CH3 domain interface. Exemplary amino acid residue substitution may include K409W, K360E, Q347E, Y349S, and/or S354C in a first CH3 domain, and D399V, F405T, Q347R, E357W, and/or Y349C in a second CH3 domain.
PNG
media_image3.png
302
250
media_image3.png
Greyscale
As to claim 3 and 5, at least one of the binding moieties is an antibody fragment (Fab or VHH) as set forth in Figure 2C with antibody-like properties.
As to claim 4, Woning et al. teach the antibody fragment can be divalent such as an Fab [0030] or monovalent comprising a single domain antibody such as a camelid single domain antibody [0057].
As to claim 6, Woning et al. teach [0081] that modified forms of antibody-like structures may be included such as a fusion protein comprising at least one heavy chain portion lacking a CH2 domain and comprising a binding domain of a polypeptide comprising the binding portion of one member of a receptor ligand pair which encompasses “any receptor-protein”.
As to claims 8-9, Woning et al. teach [0113] that at least one amino acid residue of the CH2 domain of the recombinant proteinaceous binding molecule that is able to mediate binding to Fc receptors is “lacking or mutated” where the mutation is Asn297->Ala (N297A).
As to claims 14, Woning et al. teach [0122] pharmaceutical compositions comprising the recombinant proteinaceous binding molecule.
As to claims 15-16, and 21, such claims are drawn to the recombinant proteinaceous binding molecule per se as the use of the binding molecule for treatment or diagnosis is only an intended use and does not bear patentable weight.
As to claims 17-20, Woning et al. teach [0115-0116], nucleic acids encoding the recombinant proteinaceous binding molecule, vectors and host cells comprising said nucleic acids, and methods of producing the recombinant proteinaceous binding molecule.
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:
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.
Claim(s) 7 is further rejected under 35 U.S.C. 103 as being unpatentable over Woning et al (US20190218310, published 7-18-2019, filed 12-22-2017) in view of Akiba et al. (Antibody Therapeutics, Volume 2, Issue 3, July 2019, Pages 65–69) and Bardroff et al. (US20190002589A1, published 01/03/2019).
Claim 7 is drawn to the specific amino acid changes to support the “knob-in-hole” structure and stabilization of the bispecific antibody. The claim is drawn to the recombinant proteinaceous binding molecule of claim 1, wherein the immunoglobulin CH3 domain of the first or the second heavy chain comprises at least one of the amino acid substitutions T366S, L368A and Y407V (CH3 hole-chain) and the immunoglobulin CH3 domain of the second heavy chain comprises the amino acid substitution T366W (CH3 knob-chain), wherein the CH3 hole-chain further comprises the amino acid substitution Y349C and the CH3-knob chain further comprises the amino acid substitution S354C.
Woning et al. teach [0009] that binding molecule modifications include the “knobs-into-holes” (KiH) approach which involves the introduction of a bulky residue into one of the CH3 domains of one of the antibody heavy chains. This bulky residue fits into a complementary “hole” in the other CH3 domain of the paired heavy chain so as to promote correct pairing of heavy chains. For example, Figure 3 and [0044] depicts a conventional Fab portion containing CH3-“hole” mutations (T366S/L368A/Y407V) and VHH portion containing a CH3 knob (T366W) mutation. Woning et al. further teach [0102] that the two Fc domains of the antigen binding construct are heterodimerized through hydrophobic interaction effects. This dimerization technique utilizes hydrophobic interactions instead of electrostatic ones to promote and strengthen Fc domain pairing in the CH3/CH3 domain interface. Exemplary amino acid residue substitution may include K409W, K360E, Q347E, Y349S, and/or S354C in a first CH3 domain, and D399V, F405T, Q347R, E357W, and/or Y349C in a second CH3 domain.
Thus, Woning et al. fully teaches every aspect of Claim 7 except for the last two mutations’ (S354C and Y349C) locations. Woning et al. doesn’t teach which mutation should go within the “knob” and which should go within the “hole”.
However, knowledge of the S354C and Y349C mutations, their locations, and their functional significance was well known prior to the effective filing date.
For example, Akiba et al. teaches (page 66, 1st column, 1st para) that one of the most promising strategies to generate Fc-fused BsAbs (bispecific antibodies) is knobs-into-holes (KiH) method originally developed by Genentech’s researchers. In this engineering system, four amino-acid mutations (T366W in the knob chain and T366S, L368A, Y407V in the hole chain) are made into a pair of different Fcs to preferentially form the heterodimer of the CH3 domains of human immunoglobulin γ1 (hIgG1). Further improvement with higher yield was achieved by introducing a disulfide bond at the heterodimer interface (S354C in the knob chain and Y349C in the hole chain).
Also, Bardroff et al. teaches [0084] that their bispecific antibodies are “hetero-dimers”, meaning that one part comes from first antibody, specific for a first target, and another part comes from a second antibody, specific for a second target. A “hetero-dimerization modification” is a modification to one or both parts of the antibodies forming the hetero-dimeric bispecific antibody, intended to facilitate such formation. An example of hetero-dimerization modifications of the Fc domains of two IgG1 parts of antibodies intended to form a bispecific is a “knob” with a bulky amino acid (aa) side chain (S354C, T366W) in the first heavy chain and a “hole” with small aa side chains (Y349C, T366S, L368A, Y407V) were introduced in the second heavy chain as well as an additional disulfide bridge in the CH3 region connecting both heavy chains.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to have modified the bispecific antibody of Woning et al. by selecting the “knob” to have the S354C and the “hole” to have the Y349C mutation as these mutations were well-known to be included with “knob-in-hole” modifications, and it was also well-known which mutation went with the knob and which went into the hole according to the teachings of Akiba et al. and Bardroff et al. Further, one would have been motivated to do so because Akiba et al. further taught that by incorporating these two mutations (to form a disulfide bond) one could achieve a higher yield of product and Woning et al. taught that this dimerization technique utilizes hydrophobic interactions instead of electrostatic ones to promote and strengthen Fc domain pairing in the CH3/CH3 domain interface. Thus, the entirety of claim 7 is prima facie obvious.
Second anticipatory Rejection.
Claim(s) 1-5, 10-11, 13-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xing et al. (“BiHC, a T-Cell–Engaging Bispecific Recombinant Antibody, Has Potent Cytotoxic Activity Against Her2 Tumor Cells; Translational Oncology, Vol. 10, Issue 5, October 2017).
As to claims 1-2, Xing et al. teach a bispecific antigen binding construct which comprises a binding moiety capable of binding an antigen that is linked to an IgG Fc fragment and a variable domain of an antibody heavy chain that targets a second antigen linked to IgG Fc fragment with knob in hole construction in the CH3 domain of the Fc fragment. See Figure 1A-B. Xing et al. further teach that the antibody has knobs-in-hole modifications. See Materials & Methods. BiHC was formed via the heterodimerization of VH-VL (anti-CD3)-CH2CH3 (T366S, L368A, Y407V, Hole mutant) and anti-Her2 VHH-CH2CH3 (T366W, Knob mutant).
PNG
media_image4.png
146
700
media_image4.png
Greyscale
As to claim 3 and 5, at least one of the binding moieties is an antibody fragment (ScFv or VHH) as set forth in Figure 1B with antibody-like properties.
As to claim 4, Xing et al. teach the antibody fragment can be monovalent such as a ScFv or comprising a camelid single domain antibody (VHH) (Figure 1B and Materials and Methods).
As to claims 10 and 13, Xing et al. teach that one of the binding sites of the bispecific antibody binds to a tumor-associated antigen (Her2- Figure 1B) and that second binding site (scFv) comprises a heavy chain of a second binding site that targets CD3.
As to claim 11, Xing et al. teach that one arm of the bispecific antibody is a scFV specific for CD3. Xing et al. further teach (see Expression and purification of BiHC from E.coli) that “to engage T-cells, the ScFv of anti-CD3 clone UCHT1 was used”. A sequence search of SEQ ID NO:2 revealed that SEQ ID NO:2 is a fusion protein comprising an anti-CD3 antibody clone UCHT1 VL, a linker, and a human IgG1 Fc hole mutant. Absent evidence to the contrary, the light chain of Xing’s anti-CD3 ScFv has at least 80% identity to SEQ ID NO:2.
As to claims 14, Xing et al. teach in-vivo efficacy studies comprising pharmaceutical compositions of the bispecific antibody (mice were treated with BiHC (5 mg/kg) or PBS alone).
As to claims 15-16, and 21, such claims are drawn to the recombinant proteinaceous binding molecule per se as the use of the binding molecule for treatment or diagnosis is only an intended use and does not bear patentable weight.
As to claims 17-20, Xing et al. teach [Materials and Methods] nucleic acids encoding the recombinant proteinaceous binding molecule were synthesized and cloned into pET21 or pET26b plasmid vectors and recombinantly expressed in host cells.
Noted art not currently relied upon:
US 20250101103 A1 summarizes the following:
[0006] One approach which overcomes some of the aforementioned shortcomings is described in WO2013/104804 [JULIUS-MAXIMILIANS-UNIVERSITÄT WÜRZBURG] and refers to “DUAL ANTIGEN-INDUCED BIPARTITE FUNCTIONAL COMPLEMENTATION” or the “HEMIBODY® approach. As parts of the aforementioned approach, two polypeptides are designed, each composed of a targeting moiety (e.g. a single-chain variable fragment (scFv) or an antibody Fab fragment) fused to either the variable light chain domain (VL) or the complementary variable heavy chain (VH) domain of a splitted or dissected T cell-activating anti-CD3 antibody Fv domain. The unpaired VH and VL domain (e.g. the split CD3 VH domain and the split CD3 VL domain) is not able to bind to CD3 alone. However, once the aforementioned two polypeptides bind to their target antigen on the surface of a cell via their targeting moiety, the complementary VL and VH domains come in close proximity and interact with each other to reconstitute the original and functional CD3 Fv domain. The thus on-target cell formed trispecific heterodimeric antibody engages and stimulates T-cells for cancer cell destruction such as a conventional trivalent trispecific antibody format.
[0007] Since its first publication, the HEMIBODY® approach has been subject to further improvements addressing pharmacokinetic questions, product homogeneity and unwanted residual heteroassocation of Hemibodies in solution in the absence of a target cell (WO2016/023909, WO2017/087789, WO2019/077092, WO2020/216883, WO2020/216879, WO2020/216878, WO2020/223108, WO2020/010104).
No claim is currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/GARY B NICKOL/Primary Examiner, Art Unit 1643
Prosecution Insights