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
Claim Status
Applicant’s amendment filed April 29, 2022 has been received and entered.
Claims 2, 5, 11, 14, and 30 have been amended.
Claims 3-4, 9-10, 15-17 and 24 have been canceled.
Claims 1-2, 5-8, 11-14, 18-23, and 25-32 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, 62/931,307 filed November 6, 2019, 62/984,731 filed March 3, 2020, and 62/991,042 filed March 17, 2020 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Instant claim 1 is drawn to a multi-specific antibody-like protein with binding domains D1-D6, wherein the antibody-like protein is either penta-specific or hexa-specific.
The specifications of prior applications 62/931,307, 62/984,731, and 62/991,042 do not disclose the subject matter of the presently claimed invention. Specifically, the prior applications do not contemplate multi-specific antibody-like proteins having six binding domains. Application 62/931,307 is directed to penta-specific antibodies, 62/984,731 is directed to CD19 antibodies, and 62/991,042 is directed to multi-specific antibodies including penta-specific antibodies, however none of the applications contemplate a multi-specific antibody comprising six binding domains. In addition, the prior applications do not disclose tumor associated antigens (TAA) SIRPa, HER4, CLAUDIN 18.2C, CMET, and CD226 (claim 14), nor do they contemplate the product being used to treat infectious or autoimmune diseases (claim 30). Accordingly, the instant application is not entitled to the benefit of provisional applications 62/931,307, 62/984,731, and 62/991,042.
Should Applicant disagree with the examiner’s factual determination as to the disclosure of the various claim limitations, Applicant may point out the particular places within applications 62/931,307, 62/984,731, and 62/991,042 which discloses the specific subject matter.
Accordingly, Application PCT/US2020/059230 with the filing date of November 5, 2020 will be used for the purpose of applying art.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 29, 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1, 6-8, 14, 21, and 31 are objected to because of the following informalities:
Claims 1 and 6-8 recite “N-terminal” and/or “C-terminal”, however it should read “N-terminus” and/or “C-terminus”.
Claim 14 recites “Mesothelin”, which should not be capitalized.
Claim 21 recites “the D4 comprise a 4-1BBL”, however it should read “comprises”.
Claim 31 recites “amid bond”, however it should read “amide bond”.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites a multi-specific antibody-like protein having a N-terminus and a C-terminus, comprising in tandem from the N-terminus to the C-terminus, a first binding domain (D1) at the N-terminus, a second binding domain (D2), a Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C-terminus. The phrase “in tandem” is being interpreted as D1-D2-Fc-D3-D4 are adjacent to each other on the same polypeptide chain.
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.
Claim 30 is rejected under 35 U.S.C. 112(a), as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 Fed 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, limited working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
Claim 30 is drawn to a method for treating or “preventing a cancer, autoimmune disease, or infectious disease”, however the specification does not provide a specific definition for “preventing a cancer, autoimmune disease, or infectious disease”. Therefore, plain meaning of the term preventing, “preventing a cancer, autoimmune disease, or infectious disease” as recited in claim 30 will be interpreted as including up to 100% prevention (see Merriam Webster definition: prevent. Accessed online 29 May 2025).
The state of the art teaches that prevention of cancer has yet to be achieved. Umar et al. (2012), teaches cancer prevention remains a promising strategy for reducing the mortality and incidence rates of cancer, however, is more about reducing risk factors than it is about eliminating cancer (Abstract). In addition, Umar and Bode et al. (2009), teach cancer prevention is not about eliminating cancer altogether but reducing risk factors and exposure with the goal of inhibiting progression of cancer to more invasive stages (Umar et al., pg. 835, col. 2, par. 2; pg. 836, col. 1, par. 2; pg. 839, col. 2, par. 2-3) (Bode et al., pg. 511, col. 3, par. 2). Moreover, Sarfati et al. (2022) teaches that primary prevention of cancer through eradication or mitigation of modifiable risk factors is the best hope of reducing the future cancer burden (Sarfati et al., pg. 541, col. 1, last par.). For example, Umar teaches stopping tobacco use is one lifestyle change that can reduce both the risk of selected cancers and other diseases but does not 100% prevent cancer (Umar et al., pg. 836, col. 1, par. 2). Bode provides another example in which regular administration of celecoxib demonstrated reduced numbers of colorectal polyps while difluoromethylornithine had significant efficacy in preventing colon polyp recurrence (Bode et al., pg. 512, col. 2, par. 2); however, neither resulted in 100% prevention of cancer. Vaccination is another example, as seen with the hepatitis B virus (HBV) vaccine. The vaccine is aimed at reducing HBV infections and subsequent hepatocellular cancer (HCC) and has an estimated 69% reduction rate in prevention HBV-HCC (Umar et al., pg. 842, col. 1, par. 3), not 100% prevention. Although cancer vaccines can serve as preventive measures in high-risk populations and provide treatment options for individuals already diagnosed with cancer (Kaczmarek et al., 2023, pg. 2, par. 2), they also face a myriad of obstacles depending on the target, type of vaccine, delivery method, and cancer (Kaczmarek et al., pg. 21, section 7). Accordingly, the state of the current art is that cancer cannot be 100% prevented and there is a high degree of unpredictability in methods directed to prevention.
Regarding the scope of any cancer, there remains no evidence of 100% prevention associated with guidance and navigation control proteins.
Applicant has not provided any examples of treatment with a penta-specific or hexa-specific GNC antibody-like protein or provided an example of 100% cancer prevention or guidance on how to achieve 100% prevention.
Accordingly, in the absence of substantive direction or guidance in the instant specification, the entire scope of experimentation required to 100% prevent any cancer would be unnecessarily improper, extensive, and undue.
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.
Claims 1-2, 5-8, 18-23, and 25-32 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 1 is drawn to an antibody-like protein, which suggests that antibody regions are required (e.g., VH and VL regions), however, the claim does not recite specific antibody regions making it unclear whether the product of claim 1 it encompasses any structure as long as it binds to a tumor antigen and/or an immune signaling antigen.
Claims 2, 5-8, 18-23, and 25-32 are included in the rejection as they depend from claim 1 and fail to clarify the issue.
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 1-2, 5-8, 11-14, 18-23, and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (WO 2019/191120 A1) (“Zhu(a)”).
The instant claims are drawn to a multi-specific antibody-like protein, and nucleic acids encoding the same, having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first binding domain (D1) at the N-terminal, a second binding domain (D2) comprising a light chain moiety, a Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C-terminal, wherein the light chain moiety comprises a fifth binding domain (D5) covalently attached to the C-terminal, a sixth binding domain (D6) covalently attached to the N-terminal, or both, and wherein the D1, D2, D3, D4, D5 and D6 each has a binding specificity to a tumor antigen, an immune signaling antigen, or a combination thereof, wherein D2 is a receptor such as NKG2D, or wherein D2 binds CD3 or a tumor associated antigen (TAA). Further the multi-specific antibody-like protein D1,D2, D3, D4, D5, and D6 is a scFv domain, a receptor, a ligand, or binding specificity to an antigen selected from a receptor on a T cell, an immune checkpoint receptor, a co-stimulation receptor, a receptor of a lymphocyte or a myeloid cell, a tumor associated antigen (TAA), a tissue antigen, a neoantigen, a tumor-specific antigen (TSA), a glycoprotein, or a combination thereof. The binding domain for the receptor on the T cell is adjacent to the binding domain for the tumor associated antigen (TAA) or the binding domain for the receptor of a lymphocyte. The receptor on the T cell comprises CD3; and the immune checkpoint receptor, co-stimulating receptor, and TAA comprises those recited in claim 14. Further, wherein the D1 has a binding specificity to CD3, CD20, EGFR, D2 has the binding specificity to EGFR, CD3, HER2, MSLN, NKG2D ligands, D3 has a binding specificity to PD-L1, D4 comprises a 4-1BBL trimer or has a binding specificity to 4-1BB, D5 has a binding specificity to HER3, CD19, NKG2D ligands, and D6 has a binding specificity to CD19. A guidance and navigation control protein, comprising a dimer of the multi-specific antibody-like protein.
Zhu(a) discloses guidance and navigation control (GNC) proteins, and nucleic acids encoding said proteins [pg. 4], with multi-specific antigen binding activities to the surface molecules of a T cell and a tumor cell, comprising a binding domain for a T cell activating receptor, a binding domain for a tumor associated antigen (TAA), a binding domain for an immune checkpoint receptor, and a binding domain for a T cell co-stimulating receptor [pg. 3]. The GNC proteins can be formulated in a pharmaceutical composition in a pharmaceutically acceptable carrier for treating cancer [pg. 6].
Zhu(a) teaches the GNC multi-specific proteins comprise a CD3 T cell activating receptor; a T cell co-stimulating receptor selected from 4-1BB, CD28, OX40, GITR, CD40L, ICOS, , CD27, and CD30; an immune checkpoint receptor selected from PD-L1, PD-1, TIGIT, TIM-3, LAG-3, CTLA4, BTLA, VISTA, PDL2, CD160, LOX-1, siglec-15, and CD47; and a TAA selected from ROR1, CD19, EGFRVIII, BCMA,
CD20, CD33, CD123, CD22, CD30, CEA, HER2, EGFR, LMP1, LMP2A, mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, and TROP2. The TAA may also be a receptor on various cell types, including B cells [pg. 3]. The GNC protein may also include a NK cell receptor, such as NKG2D [pg. 5].
The GNC multi-specific protein can be an antibody or an antibody monomer that comprises an Fc domain that can optionally contain an antigen binding site. The GNC proteins can also comprise Fab fragments that contain the constant domain of the light chain and the first constant domain (CH1) of the heavy chain [pg. 19].
Zhu(a) teaches several embodiments wherein the binding domain for the tumor associated antigen is not adjacent to the binding domain for the T cell co-stimulating receptor and the binding domain for the T cell activating receptor is adjacent to the binding domain for the TAA [pg 3]. For example, Zhu(a) teaches a GNC protein has a N-terminus and a C-terminus, comprising in tandem from the N-terminus to the C-terminus, a first binding domain for CD3, a second binding domain for EGFRVIII, an lgG Fc domain, a third binding domain for PD-L1, and a fourth binding domain for 4-1BB (Fig. 2A, shown below). Zhu(a) also teaches a first binding domain for CD3, a second binding domain for CD19, an lgG Fc domain, a third binding domain for PD-L1, and a fourth binding domain for 4-1BB [Fig. 2C and pg. 4].
PNG
media_image1.png
426
624
media_image1.png
Greyscale
The GNC proteins can include multiple antigen-specific binding domains (AgBDs) that function to direct T cells (or other effector cells) to cancer cells (or other target cells) through the binding of multiple surface molecules on a T cell and a tumor cell. Two or more AgBDs can be linked together forming bi-specific, trispecific, tetra-specific, penta-specific, hexa-specific, hepta-specific, or octa-specific proteins for use in treating cancer [pg. 8].
Zhu(a) teaches a GNC protein with two AgBDs may simultaneously bind to a surface molecule, such as CD3 on a T cell, and a tumor antigen on a tumor cell, for redirecting or guiding the T cell to the tumor cell. The addition of the third AgBD that binds to 41BB, enhances anti-CD3-induced T cell activation because 41BB is a co-stimulation factor and the binding stimulates its agonist activity to activated T cells. The addition of the fourth AgBD that binds to PD-L1 on the tumor cell, functions to block the inhibitory pathway of PD-L1 mediated through its binding to PD-1 on the T cells. With these basic principles, GNC proteins may be designed and constructed to acquire multiple AgBDs specifically for binding unequal numbers of T cell antagonists and agonists, not only to re-direct activated T cells to tumor cells but also to control their activity in vivo. Therefore, the design of GNC proteins may be any multi-specific protein [pg. 9].
Zhu(a) provides examples of possible combinations of T cell activation, T cell agonist, T cell antagonist, and tumor antigen binding domains in a single GNC protein from the N-terminus to C-terminus. The GNC penta-specific protein comprises CD3 (T cell activation) + ROR1 (TAA) + PD1 (T cell antagonist) + 4-1BB (T cell agonist) + LAG3 (T cell antagonist) and the GNC hexa-specific protein comprises CD3 (T cell activation) + ROR1 (TAA) + PD1 (T cell antagonist) + 4-1BB (T cell agonist) + LAG3 (T cell antagonist) + TIM3 (T cell antagonist) [Table 2, pg. 22].
The teachings of Zhu(a) differ from the present invention in that although multi-specific GNC antibody-like proteins that are penta-specific and hexa-specific for the treatment of cancer are disclosed, the D5 and D6 binding domains are not explicitly taught as being attached to the C-terminus and the N-terminus of the D2 binding domain, respectively. Given that Zhu(a) teaches the addition of further binding domains increases the anti-cancer activity in vivo and provides examples of penta-specific and hexa-specific GNC proteins arranged in tandem from the N-terminus to the C-terminus, the skilled artisan would have a reasonable expectation of success in modifying the arrangement of the penta-specific or hexa-specific antibody-protein D5 and/or D6 binding domains to arrive at the arrangement recited in the instant claims, especially as Zhu(a) emphasizes, “it will be readily understood that the aspects of the disclosure, and illustrated in the Figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated” [pg. 8]. Accordingly, the prior art reference as combined provided a prima facie case of obviousness
Claims 1 and 26-32 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (WO 2019/191120 A1) (“Zhu(a)”) in view of claims 1-2, 5-8, 11-14, 18-23, and 25-26 above, and in further view of Zhu et al. (US 2020/0157224 A1) (“Zhu(b)”).
The instant claims are drawn to a multi-specific antibody-like protein, and nucleic acids encoding the same, having a N-terminus and a C-terminus, comprising in tandem from the N-terminus to the C-terminus, a first binding domain (D1) at the N-terminus, a second binding domain (D2) comprising a light chain moiety, a Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C-terminus, wherein the light chain moiety comprises a fifth binding domain (D5) covalently attached to the C-terminus, a sixth binding domain (D6) covalently attached to the N-terminus, or both, and wherein the D1, D2, D3, D4, D5 and D6 each has a binding specificity to a tumor antigen, an immune signaling antigen, or a combination thereof; an isolated nucleic acid sequence encoding the protein, a host cell comprising the isolated nucleic acid sequence, wherein the host cell is a prokaryotic cell or a eukaryotic cell, a method for producing a multi-specific antibody or monomer, comprising culturing a host cell comprising the isolated nucleic acid sequence, expressing the multi-specific antibody-like protein, and purifying the multi-specific antibody-like protein, an immuno-conjugate comprising a cytotoxic agent or an imaging agent linked to the multi-specific antibody through a linker, wherein the linker comprises an ester bond, an ether bond, an amide bond, a disulphide bond, an imide bond, a sulfone bond, a phosphate bond, a phosphorus ester bond, a peptide bond, or a hydrophobic poly(ethylene glycol) linker.
The teachings of Zhu(a) are set forth above including methods for treating cancer comprising administering a pharmaceutical composition comprising a multi-specific GNC protein and isolated nucleic acid sequences encoding for the multi-specific GNC protein recited in the instant claims.
Zhu(a) does not teach an expression vector comprising the isolated nucleic acid sequence, a host cell comprising the isolated nucleic acid sequence, wherein the host cell is a prokaryotic cell or a eukaryotic cell, a method for producing a multi-specific antibody or monomer, comprising culturing a host cell comprising the isolated nucleic acid sequence, expressing the multi-specific antibody-like protein, and purifying the multi-specific antibody-like protein, an immuno-conjugate comprising a cytotoxic agent or an imaging agent linked to the multi-specific antibody through a linker, wherein the linker comprises an ester bond, an ether bond, an amide bond, a disulphide bond, an imide bond, a sulfone bond, a phosphate bond, a phosphorus ester bond, a peptide bond, or a hydrophobic poly(ethylene glycol) linker.
Zhu(b) teaches GNC multi-specific antibodies and isolated nucleic acid sequences encoding the multi-specific antibody monomers, the multi-specific antibodies, or the antigen-binding fragments thereof [0020]. Zhu(b) further teaches expression vectors and host cells comprising the nucleic acid sequences, wherein the prokaryotic or eukaryotic host cell includes the expression vector [0021]. Additionally, the multispecific antibody can be used as an immuno-conjugate by linking to a cytotoxic agent or imaging agent through a linker [0022] that is an ester bond, an ether bond, an amide bond, a disulphide bond, an imide bond, a sulfone bond, a phosphate bond, a phosphorus ester bond, a peptide bond, or a hydrophobic poly(ethylene glycol) linker [0023].
It would have been obvious to one of ordinary skill at the time of filing to combine the teachings of Zhu(a) and Zhu(b). Zhu(a) teaches the multispecific GNC protein can be penta-specific or hexa-specific, and can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, however, does not provide methods for expressing and purifying the protein, or contemplate for use in an immune-conjugate. Methods for protein production and purification, and the use of proteins as immune-conjugates were well known in the art at the time of filing as evidenced by Zhu(b). Accordingly, the prior art references as combined provided a prima facie case of obviousness.
Double Patenting
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
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).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 5-8, 22-23, and 26-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 17, 19-24, 29, and 31-32 of copending Application No. 17/909,357. Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims teach a the multi-specific antibody-like protein has a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first binding domain (D1) at the N-terminal, a second binding domain (D2) comprising a light chain moiety, a Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C-terminal, wherein the light chain moiety comprises a fifth binding domain (D5) covalently attached to the C-terminal, a sixth binding domain (D6) covalently attached to the N-terminal, or both, and wherein the D1, D2, D3, D4, D5 and D6 each has a binding specificity to a tumor antigen, an immune signaling antigen, or a combination thereof, having binding specificity to CD19, further comprising a scFv domain, a Fab region, or both, wherein the scFv domain or Fab region. Further claimed is an isolated nucleic acid sequence, encoding an amino acid sequence of the multi-specific antibody-like protein, an expression vector comprising the isolated nucleic acid, a prokaryotic or a eukaryotic host cell comprising the nucleic acid, a method of producing an antibody comprising culturing the host cell, an immune-conjugate, comprising the multi-specific antibody-like protein and a cytotoxic agent or imaging agent linked via a linker, and wherein the linker comprises a covalent bond selected from an ester bond, an ether bond, an amine bond, etc.; a pharmaceutical composition, comprising the multi-specific antibody-like protein or immune-conjugate and a pharmaceutically acceptable carrier; methods for treating cancer. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 11-14, 18-21, and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 17, 19-24, 29, and 31-32 of copending Application No. 17/909,357, in view of Zhu et al. (WO 2019/191120 A1) (“Zhu(a)”) Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims teach a multi-specific antibody-like protein has a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first binding domain (D1) at the N-terminal, a second binding domain (D2) comprising a light chain moiety, a Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C-terminal, wherein the light chain moiety comprises a fifth binding domain (D5) covalently attached to the C-terminal, a sixth binding domain (D6) covalently attached to the N-terminal, or both, and wherein the D1, D2, D3, D4, D5 and D6 each has a binding specificity to a tumor antigen, an immune signaling antigen, or a combination thereof, having binding specificity to CD19, further comprising a scFv domain, a Fab region, or both, wherein the scFv domain or Fab region. Further claimed is an isolated nucleic acid sequence, encoding an amino acid sequence of the multi-specific antibody-like protein, an expression vector comprising the isolated nucleic acid, a prokaryotic or a eukaryotic host cell comprising the nucleic acid, a method of producing an antibody comprising culturing the host cell, an immune-conjugate, comprising the multi-specific antibody-like protein and a cytotoxic agent or imaging agent linked via a linker, and wherein the linker comprises a covalent bond selected from an ester bond, an ether bond, an amine bond, etc.; a pharmaceutical composition, comprising the multi-specific antibody-like protein or immune-conjugate and a pharmaceutically acceptable carrier; methods for treating cancer.
The instant claims differ from the copending claims in that they do not recite D1,D2, D3, D4, D5, and D6 are independently a scFv domain, a receptor, or a ligand, or wherein the D1, D2, D3, D4, D5, and D6 independently has a binding specificity to an antigen selected from a receptor on a T cell, an immune checkpoint receptor, a co-stimulation receptor, a receptor of a lymphocyte or a myeloid cell, a tumor associated antigen (TAA), a tissue antigen, a neoantigen, a tumor-specific antigen (TSA), or a glycoprotein; the arrangement of the TAA in relation to the T cell or lymphocyte receptors; specific examples of immune checkpoint receptors, co-stimulating receptors, or TAA; or that the multi-specific antibody-like protein can dimerize.
Zhu(a) teaches the GNC multi-specific proteins comprise a CD3 T cell activating receptor; a T cell co-stimulating receptor selected from 4-1BB, CD28, OX40, GITR, CD40L, ICOS, , CD27, and CD30; an immune checkpoint receptor selected from PD-L1, PD-1, TIGIT, TIM-3, LAG-3, CTLA4, BTLA, VISTA, PDL2, CD160, LOX-1, siglec-15, and CD47; and a TAA selected from ROR1, CD19, EGFRVIII, BCMA, CD20, CD33, CD123, CD22, CD30, CEA, HER2, EGFR, LMP1, LMP2A, mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, and TROP2. The TAA may also be a receptor on various cell types, including B cells, and The binding domain for the receptor on the T cell is adjacent to the binding domain for the tumor associated antigen (TAA) or the binding domain for the receptor of a lymphocyte. Zhu(a) further teaches the GNC multi-specific proteins can be linked together. Therefore, it would have been obvious to skilled artisans to modify the generic methods of the copending claims to include the specific receptors and TAA as recited in the instant claims. Artisans would have more than a reasonable expectation of success in doing so given that the prior art of Zhu(a) teaches penta-specific and hexa-specific GNC proteins for the treatment of cancer targeting the same receptors and TAA as recited in the instant claims. As such, the instant claims are either anticipated and/or rendered obvious by the copending claims in view of Zhu(a).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5-8, 11-14, 18-23, and 25-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-9, 11-20, 23-25, and 27-32 of copending Application No. 17/909,358. Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims teach a multi-specific antibody-like protein having a N- terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first binding domain (D1) at the N-terminal, a Fab region as a second binding domain (D2) comprising a light chain, a Fc region, a third binding domain (D3) having a binding affinity to PD-L1, and a fourth binding domain (D4) having a binding affinity to 4-1BB at the C-terminal, wherein the light chain comprises a fifth binding domain (D5) covalently attached to the C-terminal and a sixth binding domain (D6) covalently attached to the N-terminal, and wherein D1, D2, D5, and D6 each independently has a binding affinity to a tumor associated antigen (TAA) or CD3; wherein D1 or D2 bind CD3; wherein the D1, D3, D4, D5, and D6 is independently a scFv domain, a receptor, or a ligand; wherein the D1 has a binding specificity against CD3, D2 has a binding specificity against EGFR, EGFRvIII, CD20, mesothelin, Claudin18.2, HER2, CD33or a combination thereof, D3 has a binding specificity against PD-L1, D4 has a binding specificity against 4-1BB, and D5 and D6 each independently has a binding specificity against a tumor associated antigen; D1 has a binding specificity against CD3, D2 has a binding specificity against a tumor associated antigen, D3 has a binding specificity against PD-L1, D4 has a binding specificity against 4-1BB, and D5 and D6 each independently has a binding specificity against NKG2D ligands, HER3, CD19 or a combination thereof; wherein the D1 has a binding specificity against EGFR, D2 has a binding specificity against CD3, D3 has a binding specificity against PD-L1, D4 has a binding specificity against 4-1BB, and D5 has a binding specificity against CD19, and D6 has a binding specificity against HER3; wherein D1-D6 further comprise the binding specificities recited in claims 7-9 and 11-19; wherein the multi-specific antibody-like protein having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, optionally a first binding domain (D1) at the N-terminal, a second binding domain (D2) comprising a light chain, wherein the light chain optionally comprises a fifth binding domain (D5) covalently attached to the C-terminal, a sixth binding domain (D6) covalently attached to the N-terminal, or both, a Fc region, optionally a third binding domain (D3), and optionally a fourth binding domain (D4) at the C-terminal, wherein at least one of D1, D2, D3, D4, D5, and D6 is a NKG2D, and wherein D1, D2, D3, D4, D5, and D6 each independently has a binding affinity to specificity against a T cell activating receptor, an immune cell receptor, an immune checkpoint molecule, a co-stimulation factor, a receptor of a leukocyte, a tumor antigen, a tumor associated antigen (TAA), a receptor of a tissue cell, a receptor of a cancer cell; wherein the binding domain for a T cell activating receptor is adjacent to the binding domain for a tumor associated antigen (TAA); wherein the D1, D2, D3, D4, D5 and D6 each independently has a binding specificity against an antigen selected from those recited in claim 24-25; isolated nucleic acid sequences encoding for the multi-specific antibody-like protein, an expression vector comprising the isolated nucleic acid sequence, a prokaryotic or eukaryotic host cell comprising the isolated nucleic acid sequence, a method for producing a multi-specific antibody or monomer, comprising culturing a host cell comprising the isolated nucleic acid sequence, expressing the multi-specific antibody-like protein, and purifying the multi-specific antibody-like protein, an immuno-conjugate comprising a cytotoxic agent or an imaging agent linked to the multi-specific antibody through a linker, wherein the linker comprises an ester bond, an ether bond, an amide bond, a disulphide bond, an imide bond, a sulfone bond, a phosphate bond, a phosphorus ester bond, a peptide bond, or a hydrophobic poly(ethylene glycol) linker. As such, the instant claims are either anticipated and/or rendered obvious by the copending claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5-8, 11-14, 18-23, and 25-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-13, 15-18, 22, and 24 of copending Application No. 16/615,123, in view of Zhu et al. (WO 2019/191120 A1) (“Zhu(a)”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims teach a tetra-specific antibody monomer having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first scFv domain at the N-terminal, a second scFv domain, a Fab domain, an Fc domain, a third scFv at the C-terminal, wherein the first scFv domain, the second scFv domain, the Fab domain, and the third scFv domain each has a binding specificity against a different antigen, wherein the antigen is a tumor antigen, an immune signaling antigen, or a combination thereof, and wherein the first scFv domain, the second scFv domain, the Fab domain, and the third scFv domain have a binding specificity against CD19, CD3, 4-1BB, and PD-L1, respectively; wherein the tetra-specific antibody is a dimer of the tetra-specific antibody monomers. In addition the copending claims teach, an isolated nucleic acid sequence encoding the tetra-specific antibody, an expression vector comprising the isolated nucleic acid sequence, a prokaryotic or eukaryotic host cell comprising the isolated nucleic acid sequence; a method for producing a tetra-specific antibody, comprising culturing a host cell comprising an isolated nucleic acid sequence such that the DNA sequence encoding the tetra-specific antibody is expressed, and purifying said tetra-specific antibody. The copending claims also teach a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and the tetra-specific antibody for treating a human subject with a cancer, comprising administering to the subject an effective amount of the tetra-specific antibody.
The instant claims differ from the copending claims in that they do not recite the multi-specific antibody protein comprises a fifth and/or sixth binding domain (D5 and/or D6) resulting in a penta-specific or hexa-specific protein, that the first binding domain (D1) has binding specificity against CD3, CD20, or EGFR, D3 has a binding specificity to PD-L1, and D4 has a binding specificity to 4-1BB.
The teachings of Zhu(a) have been set forth above. Specifically, Zhu(a) teaches GNC proteins arranged from the N-terminus to C-terminus, including a penta-specific protein comprising CD3 (D1) + ROR1 (D2) + PD1 (D3) + 4-1BB (D4) + LAG3 (D5) and a GNC hexa-specific protein comprises CD3 (D1) + ROR1 (D2) + PD1 (D3) + 4-1BB (D4) + LAG3 (D5) + TIM3 (D6). Zhu(a) also teaches that the binding domains can be interchangeable and arranged in a variety of configurations. Given that Zhu(a) teaches the addition of further binding domains increases the anti-cancer activity in vivo and provides examples of penta-specific and hexa-specific GNC proteins arranged in tandem from the N-terminus to the C-terminus, the skilled artisan would have a reasonable expectation of success in modifying the tetra-specific antibody taught by the copending claims by the addition of D5 and/or D6 binding domains to arrive at the arrangement recited in the instant claims, especially as Zhu(a) emphasizes, “it will be readily understood that the aspects of the disclosure, and illustrated in the figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated”. As such, the instant claims are either anticipated and/or rendered obvious by the copending claims in view of Zhu(a).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 29, and 31-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-13, 15-18, 22, and 24 of copending Application No. 16/615,123, in view of Zhu et al. (WO 2019/191120 A1) (“Zhu(a)”), and further in view of Zhu et al. (US 2020/0157224 A1) (“Zhu(b)”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims teach a tetra-specific antibody monomer having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first scFv domain at the N-terminal, a second scFv domain, a Fab domain, an Fc domain, a third scFv at the C-terminal, wherein the first scFv domain, the second scFv domain, the Fab domain, and the third scFv domain each has a binding specificity against a different antigen, wherein the antigen is a tumor antigen, an immune signaling antigen, or a combination thereof, and wherein the first scFv domain, the second scFv domain, the Fab domain, and the third scFv domain have a binding specificity against CD19, CD3, 4-1BB, and PD-L1, respectively; wherein the tetra-specific antibody is a dimer of the tetra-specific antibody monomers. In addition the copending claims teach, an isolated nucleic acid sequence encoding the tetra-specific antibody, an expression vector comprising the isolated nucleic acid sequence, a prokaryotic or eukaryotic host cell comprising the isolated nucleic acid sequence; a method for producing a tetra-specific antibody, comprising culturing a host cell comprising an isolated nucleic acid sequence such that the DNA sequence encoding the tetra-specific antibody is expressed, and purifying said tetra-specific antibody. The copending claims also teach a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and the tetra-specific antibody for treating a human subject with a cancer, comprising administering to the subject an effective amount of the tetra-specific antibody.
The instant claims differ from the copending claims in that they do not teach a penta- or hexa-specific antibody-like protein, or an immuno-conjugate comprising a cytotoxic agent, or an imaging agent linked to the multi-specific antibody and pharmaceutical compositions comprising the same.
The teachings of Zhu(a) and Zhu(b) have been set forth in detail above, including methods for treating cancer comprising administering a pharmaceutical composition comprising a multi-specific GNC protein and isolated nucleic acid sequences encoding for the multi-specific GNC protein recited in the instant claims.
Zhu(a) does not an immuno-conjugate comprising a cytotoxic agent, or an imaging agent linked to the multi-specific antibody through a linker, wherein the linker comprises an ester bond, an ether bond, an amide bond, a disulphide bond, an imide bond, a sulfone bond, a phosphate bond, a phosphorus ester bond, a peptide bond, or a hydrophobic poly(ethylene glycol) linker.
Zhu(b) teaches the multispecific antibody can be used as an immuno-conjugate by linking to a cytotoxic agent or imaging agent through a linker that is an ester bond, an ether bond, an amide bond, a disulphide bond, an imide bond, a sulfone bond, a phosphate bond, a phosphorus ester bond, a peptide bond, or a hydrophobic poly(ethylene glycol) linker.
It would have been obvious to one of ordinary skill at the time of filing to combine the teachings of Zhu(a) and Zhu(b). Zhu(a) teaches the multispecific GNC protein can be penta-specific or hexa-specific, and can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, however, does not teach the protein in an immune-conjugate. The use of proteins as immune-conjugates were well known in the art at the time of filing as evidenced by Zhu(b). As such, the instant claims are either anticipated and/or rendered obvious by the copending claims in view of Zhu(a) and Zhu(b).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5-8, 11-14, 18-23, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 11, and 13 of U.S. Patent No. 12,029,761 B2 in view of Zhu et al. (WO 2019/191120 A1) (“Zhu(a)”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The issued claims teach a guidance and navigation control (GNC) protein comprising from N-terminus to C-Terminus a binding domain for a CD3 T cell activating receptor, an EGFRvIII, CD19, or ROR1 TAA binding domain, a PD-L1 immune checkpoint receptor, a binding domain for a 4-1BB T cell co-stimulating receptor, wherein the binding domain for the tumor associated antigen is not adjacent to the binding domain for the T cell co-stimulating receptor and wherein the binding domain for the T cell activating receptor is adjacent to the binding domain for the TAA, or N-terminal to the C-terminal the binding domain for 4-1BB, the binding domain for PD-L1, IgG Fc domain, the binding domain for ROR1, and the binding domain for CD3; and a pharmaceutically acceptable carrier.
The instant claims differ from the issued claims in that they do not teach a fifth or sixth binding domain (D5 and D6) resulting in a penta-specific or hexa-specific GNC protein, D2 comprises receptor or Fab region, D1-D6 can be a scFv domain, a receptor, or a ligand.
The teachings of Zhu(a) are set forth above. Specifically, Zhu(a) teaches multi-specific GNC antibody-like proteins that are penta-specific and hexa-specific for the treatment of cancer, however, the D5 and D6 binding domains are not explicitly taught as being attached to the C-terminus and the N-terminus of the D2 binding domain, respectively. Given that Zhu(a) teaches the addition of further binding domains increases the anti-cancer activity in vivo and provides examples of penta-specific and hexa-specific GNC proteins arranged in tandem from the N-terminus to the C-terminus, the skilled artisan would have a reasonable expectation of success in modifying the arrangement of the penta-specific or hexa-specific antibody-protein D5 and/or D6 binding domains to arrive at the arrangement recited in the instant claims, especially as Zhu(a) emphasizes that the GNC multi-specific proteins can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated. As such, the instant claims are either anticipated and/or rendered obvious by the patented claims in view of Zhu(a).
Claims 1 and 26-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 11, and 13 of U.S. Patent No. 12,029,761 B2, in view of Zhu et al. (WO 2019/191120 A1) (“Zhu(a)”), and in further view of Zhu et al. (US 2020/0157224 A1) (“Zhu(b)”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The issued claims teach a guidance and navigation control (GNC) protein comprising from N-terminus to C-Terminus a binding domain for a CD3 T cell activating receptor, an EGFRvIII, CD19, or ROR1 TAA binding domain, a PD-L1 immune checkpoint receptor, a binding domain for a 4-1BB T cell co-stimulating receptor, wherein the binding domain for the tumor associated antigen is not adjacent to the binding domain for the T cell co-stimulating receptor and wherein the binding domain for the T cell activating receptor is adjacent to the binding domain for the TAA, or N-te