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 September 2, 2022 has been received and entered.
Claims 1-3, 10, 22, and 26-32 have been amended.
Claim 33 has been canceled.
Claims 1-32 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. This application is a 371 of PCT/US21/22849 filed on March 17, 2021, which claims the benefit of U.S. Provisional Application 62/991,042 filed on March 17, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 3, 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
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. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The instant specification recites SEQ ID NOs: 309-334 which were not included in the current Sequence Listing for the instant application.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Objections
Claims 1-32 are objected to because of the following informalities:
Claims 1, 10, and 20 recites “a N-terminal” and “a Fc region”, however they should read “an N-terminus” and “an Fc region”.
Claims 1, 10, and 20 recite “N-terminal” and/or “C-terminal”, however they should read “N-terminus” and/or “C-terminus”.
Claims 2-9, 11-19, and 21-32 – the claims recite reference to an independent claim which should not be capitalized. For example, claim 2 recites the “multi-specific antibody protein of Claim 1”.
Claims 3, 10, 22, and 26 recite SEQ ID NO followed by a period (SEQ ID NO.), however, should be followed with a colon – “SEQ ID NO:” in accordance with 37 CFR 1.821(d). In addition, the SEQ ID NOs should be listed in numerical order.
Claim 4 recites “wherein the D1, D3, D4, D5, and D6 is independently a scFv domain…”, however should read “wherein the D1, D3, D4, D5, and D6 are independently an scFv domain…”.
There are two different claims numbered as claim 5 (but no claim 6). The second claim 5 is assumed to be claim 6.
Claim 5 (line 3) is missing a space and a comma after the group – “…CD33, or a combination thereof”.
Claims 5-6, 12, 14-15, and 18 recite “tumor associated antigen”, however should read as “tumor associated antigen (TAA)”.
Claim 6 (line 4) is missing a comma after the group – “…CD19, or a combination thereof”
Claim 10 (line 10) recites “wherein multi-specific antibody-like protein comprise an amino acid sequence”, however it should read “wherein the multi-specific antibody-like protein comprises an amino acid sequence”.
Claim 20 recites a NKG2D, however should read “an NKG2D”.
Claim 20 (line 4) is missing a space in between “domain” and “(D2)”.
Claim 24 recites “Mesothelin”, which should not be capitalized.
Claim 24 (line 7) has 2 commas after “CD38”.
Claim 25 (line 2) is missing a comma after the group – “…4-1BB, or a combination thereof”
Claim 30 recites “amid bond”, however it should read “amide bond”.
Appropriate correction is required.
Claim Interpretation
Claims 3, 10, 22, and 26 recite the multi-specific antibody-like protein comprises amino acid sequences having sequence identity to the specific SEQ ID NOs recited in the claims. For the purpose of examination, the phrase “having sequence identity” is being interpreted to mean the multi-specific antibody-like protein comprises amino acid sequences that are 100% identical to the SEQ ID NOs recited in the instant claims.
Claim 10 recites “wherein the light chain optionally comprises a fifth binding domain (D5) covalently attached to the C-terminal or a sixth binding domain (D6) covalently attached to the N-terminal. It is being interpreted that the antibody-like protein recited in claim 10 allows for either (D5) or (D6) binding domains, but not both binding domains.
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.
Claims 1-3 and 5-32 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.
Claims 1, 10, and 20 are drawn to an antibody-like protein, which suggests that antibody regions are required (e.g., VH and VL regions), however, the claims do not recite specific antibody regions making it unclear whether the products of claims 1, 10, and 20 encompass any structure as long as it binds the targets recited in the instant claims.
Claims 2-3, 5-9, 11-19, and 21-32 are included in the rejection as they depend from a rejected independent claim and fail to clarify the issue.
Claim 3 recites amino acid SEQ ID NOs, including SEQ ID NOs: 332, 334, 324, 326, 328, and 330, which are not included in the current Sequence Listing. Therefore, one of ordinary skill in the art would not be able to determine what part(s) of the multi-specific antibody-like protein these sequences correspond to.
Claims 5-6 recite the limitation "the multi-specific antibody monomer of claim 1". There is insufficient antecedent basis for this limitation in the claims.
Claim 5 recites D2 has a binding specificity against EGFR, EGFRvIII, CD20, mesothelin, Claudin18.2, HER2, CD33, or a combination thereof. It is unclear how a single binding domain can have specificity to two different tumor associated antigens.
Claim 31 recites the limitation "the multi-specific antibodies of claim 1". There is insufficient antecedent basis for this limitation in the claims.
Appropriate correction is required.
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, 4-6, 20-21, 23-25, and 31-32 are rejected under 35 U.S.C. 103 as being obvious over Zhu et al. (WO 2019/005641) (“Zhu (a)”).
The instant claims are drawn to a multi-specific antibody-like protein, having an 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 Fab region as a second binding domain (D2) comprising a light chain, an 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-terminus, wherein the light chain comprises a fifth binding domain (D5) covalently attached to the C-terminus and a sixth binding domain (D6) covalently attached to the N-terminus, 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 has a binding affinity to CD3; wherein the D1, D3, D4, D5, and D6 are independently an 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, or CD33; 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 (TAA); wherein D1 has a binding specificity against CD3, D2 has a binding specificity against a tumor associated antigen (TAA), 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, or CD19; wherein D2 is a dimer comprising NKG2D, wherein the antibody-like protein D1-D6 have binding specificity to the 65 antigens listed in claim 24.
Zhu(a) discloses human guidance and navigation control (GNC) antibodies, 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. 5].
Zhu(a) teaches the GNC multi-specific proteins comprise a CD3 T cell activating receptor; a T cell co-stimulating receptor 4-1BB; a PD-L1 immune checkpoint receptor, and a tumor associated antigen (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 tumor associated antigen (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 [pg. 19].
The GNC proteins include multiple antigen-specific binding domains 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 antigen binding domains can be linked together to form 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 the basic backbone of GNC multi-specific antibody like protein comprising two antigen binding domains that 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 third antigen binding domain 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 fourth antigen binding domain 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 surface of T cells. With these basic principles, GNC proteins may be designed and constructed with multiple antigen binding domains to re-direct activated T cells to tumor cells and control their activity in vivo. Therefore, the design of GNC proteins may be any multi-specific protein [pg. 8].
Figure 2 shows one embodiment comprising the D2 Fab dimer connected to D2 through CL/CH1 and the Fc domain.
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Table 2 provides examples of many possible combinations of T cell activation, T cell agonist, T cell antagonist, and tumor antigen binding domains that can be assembled in a single GNC protein from the N-terminus to C-terminus, including the binding domains recited in the instant claims . Zhu(a) teaches a GNC penta-specific protein comprising D1 - CD3 (T cell activation) + ROR1 (TAA) + PD1 (T cell antagonist) + 4-1BB (T cell agonist) + LAG3 (T cell antagonist) and a GNC hexa-specific protein comprising CD3 (T cell activation) + ROR1 (TAA) + PD1 (T cell antagonist) + 4-1BB (T cell agonist) + LAG3 (T cell antagonist) + TIM3 (T cell antagonist) [pg. 9]. Tables 1A-1D provide further examples of moieties that can be selected for the construct demonstrating the numerable possibilities which encompass those recited in the instant claims (e.g., EGFR, EGFRvlll, PSMA, EpCAM, etc.) [pg. 7-8].
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) teaches the same tumor associated antigens (TAA) as recited in the instant claims can be used in said antibodies. Furthermore, Zhu(a) emphasizes, “it will be readily understood that the aspects of the disclosure, and illustrated in the Figures, [the GNC antibodies] 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 3 are rejected under 35 U.S.C. 103 as being obvious over Zhu et al. (WO 2019/005641) (“Zhu (a)”), as applied to claims 1-2, 4-6, 20-21, 23-25, and 31-32 above, in further view of Kao et al. (US 7,560,111) (“Kao”).
The instant claims are drawn to a multi-specific antibody-like protein, having an 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 Fab region as a second binding domain (D2) comprising a light chain, an 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-terminus, wherein the light chain comprises a fifth binding domain (D5) covalently attached to the C-terminus and a sixth binding domain (D6) covalently attached to the N-terminus, and wherein D1, D2, D5, and D6 each independently has a binding affinity to a tumor associated antigen (TAA) or CD3. Further, the multi-specific antibody-like protein comprises an amino acid sequence having identity to SEQ ID NOs listed in claim 3, including SEQ ID NO: 106.
The teachings of Zhu(a) are set forth above. Although Zhu(a) teaches numerous targets for the binding domains of the multi-specific antibody-like protein, including those recited in the instant claims, Zhu(a) does not teach the amino acid sequences for any of the tumor associated antigens (TAA), including those that bind HER2.
Amino acid sequences of hundreds of tumor associated antigens (TAA) had been described in the art at the time of filing the instant invention that would be suitable for use in the multi-specific antibody-like protein. For example, Kao teaches anti-HER2 antibodies for the treatment of cancer which comprise an anti-HER2 binding domain having an amino acid sequence of SEQ ID NO: 15.
The anti-HER2 amino acid sequence of SEQ ID NO: 15 disclosed by Kao is 100% identical to SEQ ID NO: 106 as recited in the instant claims.
Accordingly, it would have been obvious to one of ordinary skill to obtain the amino acid sequences for any of the tumor associated antigens (TAA) described by Zhu(a) from those already disclosed by the prior art. One would have a reasonable expectation of success in selecting the amino acid sequence for a TAA such as HER2 (SEQ ID NO: 106) for use in a multi-specific antibody because it has been shown be effective against cancer as evidenced by Kao. Accordingly, the prior art reference as combined provided a prima facie case of obviousness.
Claims 10-14 and 17-19 are rejected under 35 U.S.C. 103 as being obvious over Zhu et al. (WO 2019/005641) (“Zhu (a)”), as applied to claims 1-2, 4-6, 20-21, 23-25, and 31-32 above, in further view of Blein et al. (US 9,493,563) (“Blein”).
The instant claims are drawn to a multi-specific antibody-like protein, having an 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 Fab region as 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-terminus or a sixth binding domain (D6) covalently attached to the N-terminal, a Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C-terminus; wherein D2, D5, and D6 each independently has a binding affinity to a tumor associate antigen (TAA); wherein the 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, and D4 has a binding specificity against 4-1BB; wherein the D1 has a binding specificity against CD3, D2 has a binding specificity against an antigen selected from a group consisting of EGFR, HER2, CD19, CD20, CD22, CD30, CD22, mesothelin, GD2, and Claudin 18.2, D3 has a binding specificity against PD-L1, and D4 has a binding specificity against 4-1BB; wherein D1 has a binding specificity against CD3, D2 and D5 independently each has a binding specificity against a tumor-associated antigen, D3 has a binding specificity against PD-L1, and D4 has a binding specificity against 4-1BB; wherein the D1 has a binding specificity against CD3, D2 has a binding specificity against CD20, D3 has a binding specificity against PD-L1, D4 has a binding specificity against 4-1BB, and D5 has a binding specificity against CD19; wherein the D1 and D6 independently have a binding specificity against a tumor-associated antigen, D2 has a binding specificity against CD3, D3 has a binding specificity against PD-L1, and D4 has a binding specificity against 4-1BB; or 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 D6 has a binding specificity against CD19. Further, the multi-specific antibody-like protein comprises an amino acid sequence having identity to SEQ ID NOs listed in claim 10, including SEQ ID NO: 136.
The teachings of Zhu(a) are set forth above. Although Zhu(a) teaches numerous targets for the binding domains of the multi-specific antibody-like protein, including those recited in the instant claims, Zhu(a) does not teach the amino acid sequences for any of the tumor associated antigens (TAA), including those that bind EGFR.
Amino acid sequences of hundreds of tumor associated antigens (TAA) had been described in the art at the time of filing the instant invention that would be suitable for use in the multi-specific antibody-like protein. For example, Blein teaches bispecific antibodies for the treatment of cancer which comprise an anti-EGFR binding domain having an amino acid sequence of SEQ ID NO: 175.
The anti-EFGR amino acid sequence of SEQ ID NO: 175 disclosed by Blein is 100% identical to SEQ ID NO: 136 as recited in the instant claims.
Accordingly, it would have been obvious to one of ordinary skill to obtain the amino acid sequences for any of the tumor associated antigens (TAA) described by Zhu(a) from those already disclosed by the prior art. One would have a reasonable expectation of success in selecting the amino acid sequence for a TAA such as EGFR (SEQ ID NO: 175) for use in a multi-specific antibody because it has been shown be effective against cancer when used in a bispecific antibody format as evidenced by Blein. Accordingly, the prior art reference as combined provided a prima facie case of obviousness.
Claims 1, 7-10, and 15-16 are rejected under 35 U.S.C. 103 as being obvious over Zhu et al. (WO 2019/005641) (“Zhu (a)”) in view of Blein et al. (US 9,493,563) (“Blein”), as applied to claims 1-2, 4-6, 10, 20-21, 23-25, and 31-32 above, and in further view of Zhang et al. (Acta Biochim Biophys Sin (Shanghai), 2016; 48(1):39-48) (“Zhang”).
The instant claims are drawn to a multi-specific antibody-like protein, having an 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 Fab region as a second binding domain (D2) comprising a light chain, an 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-terminus, wherein the light chain comprises a fifth binding domain (D5) covalently attached to the C-terminus and a sixth binding domain (D6) covalently attached to the N-terminus, and wherein D1, D2, D5, and D6 each independently has a binding affinity to a tumor associated antigen (TAA) or CD3; 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 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 HER3, and D6 has a binding specificity against CD19; wherein the D1 has a binding specificity against CD3, D2 has a binding specificity against EGFR, D3 has a binding specificity against PD-L1, D4 has a binding specificity against 4-1BB, and D5 has a binding specificity against HER3, and D6 has a binding specificity against CD19; or wherein the a first binding domain (D1) at the N-terminus, a Fab region as 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-terminus or a sixth binding domain (D6) covalently attached to the N-terminal, a Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C-terminus; wherein the 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 has a binding specificity against HER3; wherein the D1 has a binding specificity against CD3, D2 has a binding specificity against EGFR or EGFRvIII, D3 has a binding specificity against PD-L1, D4 has a binding specificity against 4-1BB, and D5 has a binding specificity against HER3. The multi-specific antibody-like protein comprises an amino acid sequence having identity to SEQ ID NOs listed in claim 10, including SEQ ID NO: 136.
The teachings of Zhu(a) and Blein are set forth above.
Zhu(a) teaches numerous targets that can be used when constructing a multi-specific antibody-like protein, including EGFR and HER2. However, neither Zhu(a) or Blein teach HER3 as a tumor associated antigen (TAA).
Zhang teaches aberrant HER signaling is associated with the development of various solid tumors. Monoclonal antibodies (mAbs) and small molecule inhibitors targeting EGFR and HER2 exhibit clinical benefits in the treatment of several types of cancers, but their clinical efficacy is limited by the occurrence of drug resistance. Many types of cancer such as melanoma, breast, pancreatic, prostate, ovarian, and gastric cancers express HER3. HER3 complexes with HER2 to form a heterodimer, and activates the PI3K/AKT signaling cascade that ultimately leads to therapy resistance, such as gefitinib resistance in lung cancer cells [Introduction]. Therefore, targeting HER3 in the HER3/HER2 dimerization complex provides a promising alternative target for cancer therapeutics [Abstract].
Zhang further teaches anti-HER2 mAbs that block HER2 dimerization with HER3 are ineffective because they induce HER3 dimerization with alternative binding partners such as EGFR in both low and high HER2 expressing cancer cells, promoting cell proliferation [Introduction]. Therefore, targeting various domains of HER3 eliminates any dimerization of HER3 preventing HER3 signaling and subsequent cancer cell proliferation, migration, and invasion [Fig. 1].
The teachings of Zhu(a) differ from the instant claimed invention in that even though a multi-specific antibody-like protein comprising one or more tumor associated antigens (TAA) for the treatment of cancer is disclosed, the multi-specific antibody-like construct is not explicitly taught as having a binding domain for HER3. Given that Zhu(a) teaches 21 different tumor antigens that can be used in the multi-specific antibody-like protein construct, a skilled artisan would have a reasonable expectation of success in selecting other tumor associated antigens (TAA). It would have been obvious to one of ordinary skill in the art to select HER3 as a TAA, because HER3 expression is associated with many types of cancer as evidenced by Zhang. The person having ordinary skill in the art would be motivated to modify the protocols of Zhu(a) to incorporate HER3 versus HER2, because targeting HER2 has been shown to be ineffective, allowing free HER3 to dimerize with other partners (e.g., EGFR) promoting cell proliferation. Therefore, targeting various domains of HER3 blocks dimerization and subsequent HER3 signaling and cancer cell proliferation, migration, and invasion. Thus, the prior art provided a prima facie case of obviousness.
Claims 1 and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (WO 2019/005641) (“Zhu(a)”) in view of claims 1-2, 4-6, 20, 23-25, and 31-32 above, and in further view of Zhu et al. (US 2020/0157224) (“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 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-terminus, wherein the light chain comprises a fifth binding domain (D5) covalently attached to the C-terminus and a sixth binding domain (D6) covalently attached to the N-terminus, and wherein D1, D2, D5, and D6 each independently has a binding affinity to a tumor associated antigen (TAA) or CD3; an isolated nucleic acid sequence encoding the protein, 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, an immunoconjugate 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, wherein the proteins can be penta- or hexa-specific.
Zhu(a) does not teach an expression vector comprising the isolated nucleic acid sequence, a prokaryotic or eukaryotic host cell, an immunoconjugate comprising a cytotoxic agent or an imaging agent linked to the multi-specific antibody through a linker.
Zhu(b) teaches GNC multi-specific antibodies and isolated nucleic acid sequences encoding 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 immunoconjugate 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 the protein from an isolated nucleic acid, or contemplate for use in an immunoconjugate. Methods for protein production and purification, and the use of proteins as immunoconjugates 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.
Claims 20 and 22 are rejected under 35 U.S.C. 103 as being obvious over Zhu et al. (WO 2019/005641) (“Zhu (a)”) as applied to claims 1-2, 4-6, 20-21, 23-25, and 31-32 above, and in further view of Sahin et al. (US 9,770,487) (“Sahin”).
The instant claims are drawn to a multi-specific antibody-like protein, having an 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, 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 multi-specific antibody-like protein comprises an amino acid sequence having identity to SEQ ID NO: 196 or SEQ ID NO: 198.
The teachings of Zhu(a) are set forth above. Although Zhu(a) discloses the same targets for the antigen binding domains of the multi-specific antibody-like protein as recited in the instant claims, Zhu(a) does not teach the amino acid sequences for any of the tumor associated antigens (TAA), including those that bind CLDN18.2.
The amino acid sequences of hundreds of tumor associated antigens (TAA) had been described in the art at the time of filing the instant invention that would be suitable for use in the multi-specific antibody-like protein. For example, Sahin teaches anti-CLDN18.2 antibodies for the treatment of cancers, such as gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, and cancer of the gallbladder and metastases thereof comprising a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 32.
The anti-CLDN18.2 amino acid sequence of SEQ ID NO: 32 disclosed by Sahin is 100% identical to SEQ ID NO: 196 as recited in the instant claims.
Accordingly, it would have been obvious to one of ordinary skill to obtain the amino acid sequences for any of the tumor associated antigens (TAA) described by Zhu(a) from those already disclosed by the prior art. One would have a reasonable expectation of success in selecting the amino acid sequence for a TAA such as CLDN18.2 (SEQ ID NO: 32) as taught by Sahin for use in a multi-specific antibody because it has been shown be effective against cancer when used in a monoclonal antibody format. Accordingly, the prior art reference as combined provided a prima facie case of obviousness.
Claims 20 and 26 are rejected under 35 U.S.C. 103 as being obvious over Zhu et al. (WO 2019/005641) (“Zhu (a)”) as applied to claims 1-2, 4-6, 20-21, 23-25, and 31-32 above, and in further view of Olsen et al. (WO 2019/045856) (“Olsen”).
The instant claims are drawn to a multi-specific antibody-like protein, having an 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, 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 multi-specific antibody-like protein comprises an amino acid sequence having identity to those listed in claim 26, including SEQ ID NO: 4.
The teachings of Zhu(a) are set forth above. Although Zhu(a) discloses the same T cell activators for the multi-specific antibody-like protein as recited in the instant claims, Zhu(a) does not teach their amino acid sequences.
The amino acid sequences of multiple T cell activators had been described in the art at the time of filing the instant invention that would be suitable for use in the multi-specific antibody-like protein. For example, Olsen teaches anti-CD3 antibodies that activate CD3+ T-cells and enhance cell-mediated immune responses in the treatment of cancer and other T-cell dysfunctional disorders [0007] comprising a light chain for an isolated monoclonal antibody or an antigen binding fragment having a binding specificity to an amino acid sequence of SEQ ID NO: 51 [claim 12].
SEQ ID NO: 51 disclosed by Olsen is 100% identical to SEQ ID NO: 4 as recited in the instant claims.
Accordingly, it would have been obvious to one of ordinary skill to obtain the amino acid sequences for any of the T cell activators described by Zhu(a) from those already disclosed by the prior art. One would have a reasonable expectation of success in selecting the amino acid sequence for a T cell activator such as CD3 (SEQ ID NO: 51) as taught by Olsen for use in a multi-specific antibody because it has been shown be effective against cancer when used in a monoclonal antibody, or fragments thereof. Accordingly, the prior art reference 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 1-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7, and 22 of copending Application No. 19/263,536 in view of Zhu et al. (WO 2019/005641), Kao et al. (US 7,560,111), Blein et al. (US 9,493,563), Zhu et al. (US 2020/0157224), Sahin et al. (US 9,770,487), Olsen et al. (WO 2019/045856, and Zhang et al. (Acta Biochim Biophys Sin (Shanghai), 2016; 48(1):39-48). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims teach a guidance and navigation control (GNC) protein, comprising a cytotoxic cell binding moiety and a cancer-targeting moiety, wherein the cytotoxic cell binding moiety has a binding specificity to a T-cell receptor, a NK cell receptor, a macrophage receptor, a dendritic cell receptor, or a combination thereof, and wherein the cancer targeting moiety has a binding specificity to a cancer cell receptor, wherein the T-cell receptor comprises CD3, CD28, PDL1, PD1, 0X40, 4-1BB, GITR, TIGIT, TIM-3, LAG-3, CTLA4, CD40L, VISTA, ICOS, BTLA, Light, CD30, NKp30, CD28H, CD27, CD226, CD96, CD112R, A2AR, CD160, CD244, CECAMi, CD200R, TNFRSF25 (DR3), or a combination thereof, wherein the NK cell receptor comprises CD16, NKG2D, KIR2DS1, KIR2DS2, etc., wherein the macrophage receptor comprises TLR2, TLR4, CD16, CD64, CD40, CD80, etc., wherein the cancer cell receptor comprises BCMA, CD19, CD20, CD33, CD123, CD22, CD30, ROR1, CEA, HER2, EGFR, EGFRvIII, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TROP2, or a combination thereof, and a pharmaceutical composition comprising the therapeutic complex and a pharmaceutically acceptable carrier. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims in view of Zhu(a), Kao, Blein, Zhu(b), Sahin, Olsen, and Zhang.
This is a provisional nonstatutory double patenting rejection.
Claims 1-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 9, 22-26, and 28 of copending Application No. 17/909,360 in view of Zhu et al. (WO 2019/005641), Kao et al. (US 7,560,111), Blein et al. (US 9,493,563), Sahin et al. (US 9,770,487), and Olsen et al. (WO 2019/045856). 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-terminus and a C- terminus, comprising, a first monomer, comprising, from the N-terminus to the C-terminus, a first binding monomer, a CH1 domain, a first hinge, a first CH2 domain, and a first CH3 domain, wherein the first monomer comprises optionally a first binding domain (D1) linked to the N-terminus, a fourth binding domain (D4) linked to the C-terminus, or both, and a second monomer comprising optionally a second binding domain (D2) linked to the N-terminus, a fifth binding domain (D5) linked to the C-terminus, or both, wherein D1 has a binding specificity to CD3, CD20, CEA, HER2, EGFR, or NKG2D ligand, D2 has a binding specificity to HER3, EGFR, CD3, or CD19, D4 has a binding specificity to 4-1BB, or EGFR, and D5 has a binding specificity to PD-L1 or HER3, wherein the antibody-like protein comprises D1, D2, and D4, or D1, D2, and D5, or D1, D4, and D5, or D2, D4, and D5, or Dl, D2, D4, and D5, wherein D3 has a binding specificity to HER3, EGFR, CD3, or NKG2D ligands; an expression vector comprising isolated nucleic acid sequences encoding the multi-specific antibody-like protein, a host cell, an immunoconjugate comprising the multi-specific antibody-like protein, a pharmaceutical composition, comprising the multi-specific antibody-like protein, method for treating or preventing a cancer, an autoimmune disease, or an infectious disease in a subject. Thus, the instant claims are either anticipated and/or rendered obvious by the copending claims in view of Zhu(a), Kao, Blein, Sahin, and Olsen.
This is a provisional nonstatutory double patenting rejection.
Claims 1-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8, 17, 19-25, 29, and 31-32 of copending Application No. 17/909,357 in view of Zhu et al. (WO 2019/005641), Kao et al. (US 7,560,111), Blein et al. (US 9,493,563), Zhu et al. (US 2020/0157224), Sahin et al. (US 9,770,487), Olsen et al. (WO 2019/045856, and Zhang et al. (Acta Biochim Biophys Sin (Shanghai), 2016; 48(1):39-48). 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,