DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 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.
Priority
The instant application filed 05/31/2023 is a 371 filing of PCT/US2021/061486, filed 12/01/2021, and claims domestic benefit to US provisional applications 63/166,394, filed 03/26/2021; 63/129,372, filed 12/22/2020; and 63/120,154, filed 12/01/2020.
Status of Claims/Application
Applicant’s preliminary amendment of 05/24/2024 is acknowledged. Claims 27, 29, 31, 34, 37, 42, 48, 51, 73, 78, 80-81, 85-88, and 92-94 are amended and claims 3-26, 28, 30, 32-33, 35-36, 38-41, 43-47, 49-50, 52-72, 74, 77, 82-84, 89-91, and 95-107 are canceled. Claims 1-2, 27, 29, 31, 34, 37, 42, 48, 51, 73, 75-76, 78-81, 85-88, and 92-94 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/24/2024 and 07/29/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
The instant specification recites the sequence “(Gly4Ser)n” on page 43, lines 6 and 8 without an appropriate SEQ ID NO.
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:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, 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.
Abstract/Specification Objections
The abstract of the disclosure is objected to because of the following informality: there is a typo in the parenthesis in line 2 which states “TAA (e.g., PSMA( and CD3”. Appropriate correction to change the closing parenthesis from “(“ to “)” is required. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objection
Claim 75 recites a bispecific antibody and sequences for the scFv, linkers, and constant regions of the antibodies. Part (a) recites that the linker comprises SEQ ID NO: 156 and the immunoglobulin constant region comprises SEQ ID NO: 66 and part (b) recites that the linker comprises SEQ ID NO: 156 and the constant region comprises SEQ ID NO: 68.
Both SEQ ID NOs: 66 and 68 comprise an N-terminal amino acid sequence that is identical to SEQ ID NO: 156 (shown below).
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As claimed, the bispecific antibody comprises a repeated linker sequence. The limitations are brought to applicant’s attention in the event that the claim to two linker sequences in the same bispecific antibody is unintentional.
Appropriate clarification is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 42, 73, and 79 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 42, lines 4-5, recite “terminally differentiated T cells (Teff)”. “Teff” is an art common abbreviation for effector T cells and effector T cells are not necessarily the only type of terminally differentiated T cells. Therefore, the recitation of “Teff” in parentheticals, which is a narrower embodiment of the preceding limitation, renders the instant claim indefinite as it is unclear if the terminally differentiated cells are required to be effector T cells or if Teff is an exemplary embodiment.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 42 recites the broad recitation “terminally differentiated T cells”, and the claim also recites “Teff” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
Claims 73 and 79 recite the following limitations:
Claim 73, line 4, “optionally wherein the linker is a hinge region”;
Claim 79, lines 1-2, “optionally wherein the vector is an expression vector”; and
In both of these instances, the use of the term “optionally” renders the claims indefinite as the limitations that follow the term are narrower embodiments of a preceding limitation. As such, it is unclear if the limitations are required or are exemplary embodiments rendering the metes and bounds of the claims indefinite. See MPEP § 2173.05(c).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 27, 48, 51 and 73 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 27, the instant claim is drawn to the bispecific antibody of claim 2 and recites the functional limitation that the first and/or second scFv that binds to PSMA is “capable of binding to cynomolgus PSMA”. As such, the claim is drawn to a genus of PSMA scFv(s) that are limited by what they are capable of doing (function), not by what they are (structure).
MPEP 2173.05(g) states “Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph. In re Hyatt, 708 F.2d 712, 714, 218 USPQ 195, 197 (Fed. Cir. 1983); Ariad, 598 F.3d at 1340, 94 USPQ2d at 1167. For instance, a single means claim covering every conceivable means for achieving the stated result was held to be invalid under 35 U.S.C. 112, first paragraph because the court recognized that the specification, which disclosed only those means known to the inventor, was not commensurate in scope with the claim. Hyatt, 708 F.2d at 714-715, 218 USPQ at 197.”
The instant disclosure, however, does not provide a representative number of species of the claimed genus that is capable of performing the claimed function, nor does the disclosure identify a structure function relationship that could be used to identify which PSMA scFv(s) would be capable of performing the claimed function.
The examples of the instant disclosure tested the relative binding activity of humanized PSMA-binding domain variants using constructs tested in binding assays on CHOKI1SV cells transfected with human or cynomolgus PSMA. Bivalent binding domains were tested including PSMA01019, PSMA01020, PSMA01021, PSMA01023, PSMA01024, and PSMA01025 (page 83, Example 8) with binding results shown in Figure 5. As shown, all of the constructs were able to bind cynomolgus PSMA to some degree, although the activity varies. The constructs tested were monospecific, bivalent anti-PSMA-binding domains (page 82-83, Example 6).
These anti-PSMA scFvs, however, do not provide a representative number of species of the claimed genus. Applicant also does not provide a structure function relationship that would allow an ordinarily skilled artisan to predictably identify which PSMA scFvs would be capable of binding to cynomolgus PSMA.
The prior art also does not provide a representative number of species nor does the art provide a structure-function correlation that allows for the predictable identification of which anti-PSMA antibodies would be capable of performing the claimed function. Rather, the prior art demonstrates that antibody/scFv structure/function was unpredictable.
For instance, WO 2010/037838 (Kufer, P., and R. Toblas) 08 APR 2010 teaches that anti-CD3 monoclonal antibodies- as holds true generally for any other monoclonal antibodies- function by way of highly specific recognition of their target molecule. They recognize only a single site, or epitope, on their target CD3 molecule. For example, one of the most widely used and best characterized monoclonal antibodies specific for the CD3 complex is OKT-3. This antibody reacts with chimpanzee CD3 but not with the CD3 homolog of other primates, such as macaques, or with dog CD3. On the other hand, there are also examples of monoclonal antibodies that recognize macaque antigens, but not their human counter parts. WO’838 teaches that the discriminatory ability, i.e., the species specificity, is inherent to not only CD3 antibodies, but to monoclonal antibodies in general and is a significant impediment to their development as therapeutic agents for the treatment of human diseases (page 4, paragraph 2 – page 5, paragraph 2).
While WO’838 was focused on cross-species specific antibodies for CD3, not PSMA, the teachings of WO’838 demonstrate that monoclonal antibodies function by highly specific recognition of their target molecule and that cross-reactivity varies based on the specific antibody and the epitope to which the antibody binds. Antibody structure and specific epitope binding, however, was not, and is not, predictable.
Hummer, A.M., et al (2022) Advances in computational structure-based antibody design Current Opinion in Structural Biology 74(102379); 1-7, which was published approximately 2 years after the effective filing date of the claimed invention, demonstrates ongoing unpredictability between antibody binding and epitopes. Hummer teaches that for antibodies, the major challenge in terms of structure prediction lies in accurately predicting the structure of the complementary determining regions (CDRs), in particular CDR-H3. The CDR loops tend to form most of the binding contacts with the antigen and are thus of particular importance to model accuracy. While it has long been possible to predict structural models of the framework region with sub-angstrom accuracy using homology modeling, the diverse set of possible conformations of the CDR loops makes this less amendable to prediction with homology-based methods (page 2, left column, paragraph 2). Once structures have been obtained for the antibody and antigen, these can be used to assess binding potential. The residues involved in binding on the antibody are called the paratope and those on the antigen, the epitope. Paratope and epitope residues can be identified by solving the structure of a bound antibody-antigen pair. Current methods of paratope prediction offer reasonable accuracy. Epitope prediction has proven to be more challenging (page 2, right column, paragraphs 1-2). Hummer teaches that traditional methods for antibody development, such as deriving antibodies from hybridomas of inoculated animals or from library assembly followed by display techniques are not only costly and time consuming but also are not necessarily able to produce antibodies that bind to the desired site (epitope) on an antigen. Hummer teaches that computational antibody design methods offer a way to overcome these limitations, but are held back by the lack of accurate antibody and antigen structures (page 1, right column, paragraph 2). Hummer provides a review on how advances in protein structure prediction and other areas are bringing us closer to being able to entirely computationally designed antibodies that bind strongly to a defined epitope (page 1, right column, paragraph 3) demonstrating that in 2022 predictable structure function relationships were still not known. Hummer acknowledges this in their discussion of future directions stating that “Several challenges still remain for true computational structure-based antibody design. While there has been great progress in protein structure prediction, current methods are not yet able to accurately predict the position of the side chain atoms or structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms of accuracy and specificity (predicting the types of binding interactions for residues), will be needed to help improve docking for high-throughput virtual screening.” (page 4, right column, paragraph 3).
Hummer teaches the difficulties in predicting the relationship between antibody structure and the epitopes to which they bind demonstrating a lack of predictability in the field between antibody structure, such as those used in the antigen binding domains of scFv, and function.
The teachings of WO’838 demonstrate that cross species specificity of antibodies varies based on the antibody and is the result of the epitope to which the antibody binds. Hummer demonstrates that antibody binding is the result of the CDRs of the antibody, which form most of the binding contacts with the antigen, but that epitope binding was still not predictable even with if the paratope of the antibody could be reasonably identified. Based on these teachings, one of ordinary skill in the art would not have been able to predictably identify which anti-PSMA antibodies, or scFvs thereof, would be capable of binding to cynomolgus PSMA as such structure-function was not predictable.
Neither the instant disclosure, nor the prior art, provide a representative number of species of the claimed genus of anti-PSMA scFvs capable of binding to cynomolgus PSMA. The disclosure and prior art also do not provide a structure function correlation that would allow for the predictable identification of which PSMA antibodies would be capable of performing the claimed function. Therefore, the instant claim was found not to meet the written description requirement of 35 USC 112(a).
Regarding claims 48, 51, and 73, the claims are drawn to antibody or antigen binding fragments thereof comprising a PSMA-binding domain and a CD3-binding domain, respectively. Claims 48 and 51 recite that the binding domain comprise a VH and VL and that the VH comprises the recited amino acid sequence “and/or” the VL comprises the recited amino acid sequence. Based on the recitation of “or”, the claims encompass a scope in which the claimed antibodies or antigen binding fragments thereof only require the recited VH sequence or VL sequence which can be paired with any other VH/VL region. As such, the claims are drawn to a genus of antibodies or antigen binding fragments limited by only a single VH or VL region and claims the functional limitation of the antibodies/binding fragments binding to PSMA or CD3.
Claim 73 depends on claim 48 and further claims the antibody genus of claim 48 in a bispecific format.
The instant disclosure, however, does not describe a representative number of species of the claimed genus performing the claimed functions, nor does the disclosure identify a structure-function relationship that could be used to predictably identify which antibodies/antibody fragments, comprising what sequences could be used in order to arrive at an antibody or antigen-binding fragment thereof with the claimed functions. This is particularly the case in the absence of a full complement of 6 CDRs, specifically 3 from the heavy chain variable region and 3 from the light chain variable region, which are the art recognized binding region of antibodies.
The instant specification discloses an antibody that binds to human PSMA and comprises a VH and VL with amino acid sequence of instant SEQ ID NOs: 82 and 84, respectively, and the VH and VL CDRs thereof, and teaches their use in PSMA-binding constructs (pages 36-38). The specification further discloses antibodies that bind to CD3 and comprise a VH and VL with amino acid sequence of instant SEQ ID NO: 100 and 102, respectively, and the VH and VL CDRs thereof, and teaches their use in CD3-binding constructs (pages 40-42).
These antibodies, comprising both the VH and VL with a full complement of 6 CDRs, represent the species of the claimed genus that applicant was in possession of at the time of the effective filing date of the claimed invention. The disclosure does not provide a structure-function correlation between antibody structure and function that would allow for the predictable identification of which of the claimed VH or VL regions could be used with what other VH or VL region while maintaining the claimed functions.
The state of the art around the effective filing date of the claimed invention also does not provide a representative number of species or a predictable structure-function relationship to support the full scope of the claimed genus
For example, Chiu, M.L., et al (2019) Antibody structure and function: The basis for engineering therapeutics Antibodies 8(55); 1-80 teaches that, the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). These teachings of Chiu demonstrate that the interaction between the heavy and light chain variable domains effect the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably identify which species of the instantly claimed genus would be capable of performing the claimed functions. This is particularly the case in the absence of a full complement of heavy and light chain CDRs.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published approximately two years after the effective filing date of the claimed invention, demonstrates that antibody structure and function were still not predictable even years after the effective filing date. For instance, Rojas teaches that although variable regions share a similar global architecture, they include three protruding hypervariable loops, characterized by even larger primary amino acid sequence variability, as well as by length and conformational diversity. In functional terms, these loops are the complementarity determining regions (CDRs). The spatial array formed by the six CDRs of each antibody (three from the heavy and three from the light chain) shape a unique binding site (or paratope), able to establish an interaction network with the target antigen(s) (page 1, paragraph 1). Rojas provides a review summarizing experiences in the study and manipulation of antibody-antigen interactions through combinatorial biology (page 2, paragraph 2) and demonstrates that, even conservative point mutations in known CDRs is not predictable. For instance, Rojas teaches that epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the difference between amino acids, based on physico-chemical distance between them, mutational distance, or evolutionary exchangeability. Tolerability profile to mutations within functional epitopes does not adjust strictly to any of these rules. The critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody. For instance, sometimes only tyrosine and phenylalanine residues can be exchanged without effecting antigenicity, pointing to the relevance of their almost-identical aromatic rings, whereas in other epitopes, tyrosine and histidine are exchangeable, reflecting that two different rings can fulfill a similar functional role (page 11, paragraph 1).
Rojas demonstrates that even years after the effective filing date of the claimed invention even conservative point mutations within known CDRs were not predictable and do not lead to predictable function.
As discussed above, neither the instant disclosure, nor the prior art, provide a representative number of species of the claimed genus. The disclosure and prior art also do not provide a structure function correlation that would allow for the predictable identification of which of the claimed VH and VL could be paired with what other VH or VL regions while maintaining the claimed functions of binding to PSMA or CD3. Therefore, the instant claims were found not to meet the written description requirement of 35 USC 112(a).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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, 29, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017.
US’885 teaches a cell based assay for testing the potency of multispecific binding molecules which specifically bind a T cell antigen and a target antigen for redirected T cell mediated cellular cytotoxicity (abstract). US’885 teaches that a variety of bispecific antibody therapeutics are in development that can redirect T cell cytotoxicity (RTCC) towards tumor cells, or other target cells of interest, by cross-linking the T-cell receptor complex on the surface of T cells with tumor specific antigens, or other target antigens, expressed on the tumor or other target cell. US’885 provides a schematic of such interaction in Figure 1, which shows a multispecific binding molecule that binds selectively to T-cells and tumor cells offering a mechanism to redirect T cell cytotoxicity towards the tumor cells for the treatment of cancer (page 1, [0002]; page 2, [0022]; Fig. 1). Figure 1 of US’885 is replicated below for convenience:
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The schematic demonstrates that the antibody links the tumor cell and a T cell via a tumor antigen and CD3 on the TCR complex resulting in redirected T cell killing specifically to the tumor and death of the tumor while also releasing cytolytic granules form the T cells resulting in T cell expansion.
US’885 teaches that the multispecific binding molecules can comprise dimerized single chain polypeptides, each single chain polypeptide comprising, from amino to carboxyl terminus, a target antigen binding domain, an N-terminus linker, an immunoglobulin constant region, a C-terminus linker and a T cell antigen binding domain, e.g., a CD3 binding domain (pages 5-6, [0062]). US’885 further teaches multispecific binding molecules that recognize and bind to two or more different epitopes on two or more different antigens at the same time (page 5, [0061]).
US’885 further teaches that the target antigen can be PSMA or HER2 (page 4, [0048]).
US’885 also teaches that the binding molecules can be monovalent for one specificity and bivalent for the other, e.g., “bispecific trivalent” (page 5, [0061]).
In studies performed by US’885 to determine the utility of the redirected T-cell cytotoxicity assay for functioning as a release assay for manufacturing purposes, US’885 tested the specific activity of two partially proteolyzed bispecific molecules lacking one or two CD3 binding domains at inducing target dependent T cell cytotoxicity. The ATCC was measured and compared against an intact bispecific molecule targeting PSMA and CD3 in a chromium release assay. A schematic of the PSMA/CD3 bispecific antibodies tested are shown in Fig. 5A (page 11, [0107]; page 2, [0027], which is duplicated below.
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The “single clip” bispecific antibody shown in Fig. 5A, and tested by US’885, comprises a first polypeptide that has a PSMA binding domain, a CH2CH3 constant region, and a second binding region that binds CD3; and a second polypeptide comprising a second binding region for PSMA, and a CH2CH3 constant region. The antibody also does not comprise a second CD3 binding domain.
US’885 further tested the RTCC activity of the bispecific antibodies shown in Fig. 5A and provides the results in Fig. 5B (page 11, [0107]; page 2, [0028]), which demonstrates that the single clip antibody results in cell lysis.
US’885 teaches that the T cell (TC) antigen binding domain comprises the antigen binding region of an antibody, or a fragment there of, e.g., the TC antigen binding domain comprises: 6 CDRs of an antibody variable region, the VH and VL of an antibody, or a combination thereof. In certain aspects, the TC antigen binding domain is an scFv (page 1, [0009]). US’885 further teaches that the target antigen binding domain comprises the antigen binding region of an antibody, or a fragment thereof, e.g., the target antigen binding domain can comprise the 6 CDRs of an antibody variable region, the VH and VL of an antibody, or a combination thereof. In certain aspects, the target antigen binding domain is an scFv (page 1, [0011]).
While US’885 does not explicitly state that the “single clip” antibody was formed as a heterodimer, or that the binding domains in the bispecific antibody are scFv, these modifications would have been obvious in view of the overall teachings of US’885.
For instance, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to form a bispecific antibody, in the form of the “single clip” antibody, using dimerized single chain polypeptides and to use scFv as the tumor antigen and T cell binding domains based on the teachings of US’885. It would have been obvious to form the bispecific antibody using dimerized single chain polypeptides as US’885 teaches that the multispecific binding molecules can comprise dimerized single chain polypeptides. Additionally, US’885 teaches bispecific trivalent binding molecules that are bivalent for one specificity and monovalent for the other. An ordinarily skilled artisan would have had a reasonable expectation of success as US’885 demonstrates a bispecific trivalent binding molecule. It would have been obvious to use scFv as the binding domains as US’885 teaches that the T cell and antigen binding domains can be scFv. An ordinarily skilled artisan would have had a reasonable expectation of success as US’885 teaches scFv as an antigen binding fragment that can be used as a binding domain in the bispecific antibodies disclosed.
Regards to claim 42, the claimed functions are a mechanistic result that would flow naturally from following the suggestions of the prior art. See MPEP 2145 II. The bispecific antibody disclosed by US’885, which binds a tumor associated antigen, including PSMA, and CD3, would be capable of performing the claimed functions as evidenced by the instant disclosure, which demonstrates that an anti-PSMA x anti-CD3 bispecific antibody is capable of resulting in the claimed mechanistic outcomes (instant specification, page 115-116).
Claims 27, 31, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017 as applied to claims 1 and 2 above, and in further view of US 2018/0022819 (J. Blankenship and E.T. Sewell) 25 JAN 2018.
US’885 teaches the bispecific antibody of claim 2 as discussed in detail above.
US’885, however, does not disclose that the first and/or second PSMA scFv VH and VL comprises the claimed CDR sequences.
US’819 teaches multispecific polypeptide therapeutics that bind both PSMA-expressing cells and the T cell receptor complex on T cells to induce target dependent T cell cytotoxicity, activation, and proliferation (abstract).
US’819 teaches that the PSMA binding polypeptides further include a heterodimerization domain that is capable of heterodimerization with a different heterodimerization domain in a second, non-identical polypeptide chain that includes a second binding domain (page 17, [0132]). US’819 teaches that, in certain embodiments, a PSMA-binding polypeptide or protein, for instance, can comprise a T cell binding domain for the recruitment of T cells to target cells expressing PSMA. In certain embodiments the binding domain can comprise a binding domain that specifically binds a TCR complex or a component thereof, including CD3γ, CD3δ, and CD3ε and another binding domain that specifically binds PSMA (page 18, [0137]). US’819 also teaches polynucleotide molecules encoding the polypeptides, vectors, expression cassettes/systems, and host cells for expressing the heterodimeric proteins using conventional techniques (page 60, [0219]-[0223]). US’819 also teaches methods for inducing redirected T cell cytotoxicity against a cell expressing PSMA (page 181, claim 44).
US’819 teaches bispecific antibodies comprising the humanized anti-PSMA antibody 107-1A4 (page 60, [0214]), which comprises a heavy and light chain variable region of SEQ ID NOs: 27 and 23, respectively (page 31, Table 3), which comprise the CDRs recited in instant claims 31 and 37 as shown in the ABSS alignments below:
US’819, SEQ ID NO: 27 aligned with instant SEQ ID NOs: 70, 72, and 74:
PNG
media_image4.png
700
1139
media_image4.png
Greyscale
US’819, SEQ ID NO: 23 aligned with instant SEQ ID NOs: 76, 78, and 80:
PNG
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671
1136
media_image5.png
Greyscale
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the first and/or second anti-PSMA VH and VL in the scFv disclosed by US’885 with the anti-PSMA VH and VL disclosed by US’819. It would have been obvious to make this substitution, and an ordinarily skilled artisan would have had a reasonable expectation of success, because the VH and VL domains disclosed by US’819 bind to PSMA, which is the same target as the VH and VL disclosed by US’885. Additionally, both US’885 and US’819 teach bispecific antibodies that bind PSMA and CD3, further demonstrating a nexus among the art.
Regarding claim 27, while the combination of US’885 and US’819 do not disclose that the scFv that binds to PSMA is capable of binding to cynomolgus PSMA, the ability of an antibody to bind is a necessary property resulting from the CDRs of an antibody. As the anti-PSMA antibody of US’819 comprises the same CDRs as the antibodies demonstrated in the instant disclosure, the antibodies would naturally bind to cynomolgus PSMA. See MPEP 2112 (I).
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017 as applied to claims 1 and 2 above, and in further view of WO 2007/042261 (Kischel, R., et al) 19 APR 2007.
US’885 teaches the bispecific antibody of claim 2 as discussed in detail above.
US’885, however, does not disclose that the CD3 scFv VH and VL comprises the claimed CDR sequences.
WO’261 teaches bispecific antibodies exhibiting cross-species specificity for evaluating the in vivo safety and/or activity and/or pharmacokinetic profile of the same in non-human species and in humans. WO’261 further teaches methods of evaluating the in vivo safety and/or activity and/or pharmacokinetic profile of said bispecific antibodies exhibiting cross reactivity (abstract).
WO’261 teaches that, in order to be marketed, new candidate medication must pass through rigorous testing that is performed in both humans and animals. The aim of preclinical testing is to prove that a drug candidate works and is efficacious and safe. Specifically, the purposes of the studies is to prove that the drug is not carcinogenic, mutagenic, or teratogenic as well as to understand the pharmacokinetics of the drug. Only when safety in animals and possible effectiveness has been established in preclinical testing will the drug candidate be approved for clinical testing in humans (page 1, lines 19-27). In order to effectively test bispecific antibodies cross-species, WO’261 teaches bispecific antibodies that have cross-species specificity (page 6, lines 3-17).
WO’261 teaches an anti-CD3 antibody with cross species reactivity that binds to macaque, specifically cynomolgus CD3, comprising a VH and VL of SEQ ID NOs: 6 and 8, respectively (page 36, lines 15-21; page 117, claim 10). WO’261, SEQ ID NOs: 6 and 8 comprise the CDRs recited in instant claim 34, as shown in the ABSS alignments below:
WO’261, SEQ ID NO: 6 aligned with instant SEQ ID NOs: 88, 90, and 92:
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667
1138
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Greyscale
WO’261, SEQ ID NO: 8 aligned with instant SEQ ID NOs: 94, 96, and 98:
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700
1145
media_image7.png
Greyscale
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the VH and VL in the anti-CD3 scFv in the bispecific antibody taught by US’885 with the anti-CD3 VH and VL of WO’261. An ordinarily skilled artisan would have been motivated to make this substitution in order to test cross-reactivity for use in preclinical evaluations of safety, activity, and/or pharmacokinetic profiling. An ordinarily skilled artisan would have had a reasonable expectation of success because the VH and VL of WO’261 binds to CD3, which is the same target as the T cell targeting scFv in US’885. Additionally, both US’885 and WO’261 are teaching bispecific antibodies.
Claims 1-2, 29, 42, 78-81, 85, 87-88, and 92-94 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0273622 A1 (Tan, P. and J.W. Blankenship) 27 SEP 2018 in view of US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017.
US’622 teaches protein molecules that specifically bind to CD3 and teaches that the protein binding molecules may have a second binding domain that binds to another target. In one embodiment, the multispecific binding molecules bind both tumor antigen expressing cells and the CD3 subunit of a T cell receptor complex on T cells to induce target dependent T cell cytotoxicity, activation and proliferation. The disclosure also provides pharmaceutical compositions comprising the CD3 binding polypeptide molecules, nucleic acid molecules encoding the polypeptides, and methods of making the molecules (abstract).
US’622 further teaches that the second binding domain may be a single chain variable fragment (scFv) that binds to a tumor associated antigen including PSMA or HER2 (page 3, [0019]).
US’622 teaches that the CD3 binding polypeptide may further comprise an immunoglobulin heterodimerization domain which can comprise an immunoglobulin CH1 domain or an immunoglobulin CL domain. In some embodiments, the heterodimeric CD3 binding protein comprises: (i) a first polypeptide chain comprising, in order from amino-terminus to carboxyl-terminus or carboxyl-terminus to amino-terminus, (a) a CD3 binding domain that specifically binds human CD3, (b) a first hinge region, (c) a first immunoglobulin constant region, and (d) a first immunoglobulin heterodimerization domain; and (ii) a second polypeptide chain comprising, in order from amino-terminus to carboxyl-terminus or carboxyl-terminus to amino-terminus, (a’) a second hinge region, (b’) a second immunoglobulin constant region, and (c’) a second immunoglobulin heterodimerization domain that is different from the first immunoglobulin heterodimerization domain of the first single chain polypeptide, wherein the first and second heterodimerization domains associate with each other to form a dimer. US’622 further teaches that, in some aspects, the second polypeptide chain of the heterodimeric CD3 binding protein may further comprise a second binding domain that is amino-terminal or carboxyl-terminal to the second hinge region (page 3, [0022]).
US’622 further teaches polynucleotides, e.g., DNA or RNA, encoding the binding polypeptides (page 23, [0176]) and an expression vector comprising a first and second expression unit comprising, respectively, a first and second nucleic acid segment encoding the first and second polypeptide chains of a heterodimeric CD3 binding polypeptide. The segments are operably linked to regulatory sequences suitable for expression of the nucleic acid segments in a host cell. US’622 further teaches a recombinant host cell comprising the expression vector and a method of producing the CD3 binding polypeptide comprising culturing the recombinant host cell comprising the expression vector under conditions whereby the nucleic acid segment is expressed, thereby producing the CD3 binding polypeptide. The method may further comprise recovering the heterodimeric CD3 binding polypeptide (pages 3-4, [0025]-[0027]).
US’622 further teaches a pharmaceutical composition comprising a CD3 binding polypeptide and a pharmaceutically acceptable carrier, diluent, or excipient (page 4, [0027]).
US’622 teaches a method for inducing redirected T cell cytotoxicity (RTCC) against a cell expressing a tumor associated antigen, the method comprising: contacting said tumor associated antigen expressing cell with a CD3 binding polypeptide; wherein said contacting is under conditions whereby RTCC against the tumor associated antigen cell is induced. One aspect of the disclosure includes a method for inhibiting tumor growth in a subject in need thereof, comprising administering a therapeutically effective amount of the binding polypeptide, or a pharmaceutical composition to the subject (page 4, [0027]). US’622 further teaches that “redirected T cell cytotoxicity” and “RTCC” refer to a T cell mediated process in which a cytotoxic T cell is recruited to a target cell using a multispecific protein that is capable of specifically binding both the cytotoxic T cell and the target cell, and whereby a target-dependent cytotoxic T cell response is elicited against the target cell. Polypeptides and proteins comprising CD3-binding domains, as disclosed, and tumor antigen binding domains are capable of RTCC (page 11, [0096]). As the methods disclosed by US’622 elicit a target dependent cytotoxic T cell response against the target cell, one of ordinary skill in the art would reasonably identify that the method is enhancing an immune response in the subject.
US’622 further teaches a method for treating a disorder characterized by the overexpression of a tumor antigen, such as cancer. Examples of tumor antigens that may be recognized by bispecific CD3 binding proteins include PSMA. Generally, such methods include administering to a subject in need of such treatment, a therapeutically effective amount of a CD3 binding protein comprising a second binding domain that binds a tumor antigen (page 26, [0196]). US’622 further teaches that the multispecific polypeptide molecules induce target dependent T cell cytotoxicity, activation, and proliferation (abstract; page 1, [0003]).
US’622, however, does not teach that the bispecific antibody is bivalent for the tumor associated antigen and monovalent for CD3. US’622 does not explicitly teach that the bispecific antibody does not contain a second CD3 binding domain.
The teachings of US’885 are discussed above and, as discussed in detail above, teaches the bispecific antibody of instant claim 1.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the bispecific antibody in the products and methods of US’622 with a bispecific trivalent antibody taught by US’885. It would have been obvious to make this substitution as US’885 teaches alternative formats for dimerized bispecific antibodies, including antibodies that bind a tumor antigen and a T cell. An ordinarily skilled artisan would have had a reasonable expectation of success as US’885 demonstrates that bispecific antibodies with a trivalent format are capable of inducing cytotoxicity. Additionally, both US’622 and US’885 are teaching bispecific binding molecules that target a tumor associated antigen and a T cell antigen, including PSMA or HER2 and CD3.
Regards to claim 42, the bispecific antibody disclosed by the combination of US’622 and US’885 would be capable of performing the claimed functions as evidenced by the instant disclosure, which demonstrates that an anti-PSMA x anti-CD3 bispecific antibody is capable of performing the claimed functions (instant specification, page 115-116).
Additionally, the recited limitations are mechanistic outcomes that would flow naturally from the methods taught by the combination of US’622 and US’885 in which the bispecific antibody is administered to a subject. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Claims 1 and 86 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0135943 A1 (Boustany, L.M., et al) 09 MAY 2019 in view of US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017 and US 2019/0022205 A1(Salih, H., et al) 24 JAN 2019
US’943 teaches bispecific antibodies and methods of making and using such antibodies (abstract). US’943 teaches that the bispecific antibody, directed to two targets, can be used as an agent for detecting the presence of one or more of the targets (or a fragment thereof) in a sample. In some embodiments, the antibody comprises a detectable label. The term “biological sample” is intended to include tissues, cells, and biological fluids isolated from a subject, as well as tissues, cells, and fluids present within a subject. US’943 teaches that in vitro techniques for detection include ELISAs, western blots, immunoprecipitates, and immunofluorescence. In vivo techniques include introducing a labeled antibody into a subject, for instance a radioactive marker whose presence and location can be detected by standard imaging.
US’943, however, does not disclose the bispecific antibody of instant claim 1 or that the targets are PSMA and CD3. US’943 also does not explicitly state that the method involves contacting the sample with the antibody.
The teachings of US’885 are discussed above and, as discussed in detail above, teaches the bispecific antibody of instant claim 1.
US’205 teaches PSMA binding antibodies as well as bispecific antibodies that bind PSMA and CD3 (page 1, [0001]). US’205 teaches a method of detecting or diagnosing a disease comprising contacting a sample obtained from a subject with a, preferably, labelled antibody molecule of the invention. The sample may be blood, urine, or cerebrospinal fluid, and preferably may be a tissue sample or a biopsy sample (pages 18-19, [0140]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by US’943 to use the bispecific antibody of US’885 for the detection of target antigens PSMA and CD3 and to perform the method by contacting the sample with the bispecific antibody as taught by US’205. It would have been obvious to use the antibody of US’885 to detect PSMA and CD3 in a sample as US’943 demonstrates that such methods for detecting bispecific antigen targets in a sample were known in the prior art. The use of the bispecific antibody to detect the antigens is further supported by US’205, which teaches that such methods can be used to detect or diagnose a disease. It would have been obvious to perform the method of US’943 by contacting the sample with the bispecific antibody as US’205 demonstrates that methods of detecting are performed by contacting samples obtained from a subject with a bispecific antibody. An ordinarily skilled artisan would have had a reasonable expectation of success as the applied references are all drawn to bispecific antibodies. Additionally, US’205 teaches detection methods and PSMA x CD3 bispecific antibodies, which are the same targets as the bispecific antibodies disclosed by US’885.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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.
US 11,352,426 B2
Claims 1-2, 29, 42, 78-81, 85, 87-88, and 92-94 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 14-34 of U.S. Patent No. US 11,352,426 B2 in view of US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017 and US 2018/0273622 A1 (Tan, P. and J.W. Blankenship) 27 SEP 2018.
US’426 claims a CD3 binding protein that further comprises a second binding domain and claims that the binding protein comprises, from amino-terminus to carboxyl terminus, (i) the second binding domain, (ii) a hinge region, (iii) an immunoglobulin constant region, (iv) a carboxyl terminus linker, and (v) the CD3 binding domain. US’426 further claims that the second binding domain binds a tumor associated antigen including PSMA and HER2. US’426 claims that the binding protein induces RTCC and T cell dependent lysis of cells expressing the tumor antigen. US’426 further claims that the protein comprises an immunoglobulin heterodimerization domain comprising an immunoglobulin CH1 or CL domain. US’426 claims a method for inducing RTCC against a cell expressing the tumor associated antigen comprising contacting the cell with the CD3 binding proteins under conditions where RTCC is induced.
US’426 differs from the instantly claimed invention in that US’426 does not claim the instantly recited bispecific antibody format or the instantly claimed nucleic acids, vectors, and methods of producing the bispecific antibody.
The teachings of US’885 and US’622 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to produce the bispecific antibodies claimed in US’426 using two polypeptides with two scFv targeting the tumor associated antigen and a single scFv targeting CD3, as taught by US’885, where the bispecific antibody is formed using dimerization techniques as disclosed by US’885 and US’622. It would have been obvious to make this substitution as US’885 teaches multispecific binding molecules that have monovalent specificity for one target and bivalent specificity for the other. Additionally, US’885 demonstrates a multispecific binding peptide that has two PSMA binding region and a single CD3 binding region. An ordinarily skilled artisan would have had a reasonable expectation of success as US’885 demonstrates that such a format is capable of inducing cytotoxicity. Additionally, all of US’426, US’622, and US’885 are teaching bispecific binding molecules that target a tumor associated antigen and a T cell antigen, including PSMA or HER2 and CD3.
Claims 27, 31, and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 14-34 of U.S. Patent No. US 11,352,426 B2 in view of US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017 and US 2018/0273622 A1 (Tan, P. and J.W. Blankenship) 27 SEP 2018 as applied above, and in further view of US 2018/0022819 (J. Blankenship and E.T. Sewell) 25 JAN 2018.
US’426 modified by US’885 and US’622 teaches the bispecific antibody of claim 2 as discussed in detail above.
The combination of applied references, however, does not disclose that the first and/or second PSMA scFv VH and VL comprises the claimed CDR sequences.
The teachings of US’819 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the first and/or second anti-PSMA VH and VL disclosed by US’426 modified by US’885 and US’622 with the anti-PSMA VH and VL disclosed by US’819. It would have been obvious to make this substitution, and an ordinarily skilled artisan would have had a reasonable expectation of success, because the VH and VL domains disclosed by US’819 bind to PSMA, which is the same target as the VH and VL disclosed by US’426, US’885, and US’622. Additionally, all of US’426, US’885, US’622, and US’819 teach bispecific antibodies that bind PSMA and CD3, further demonstrating a nexus among the art.
Regarding claim 27, while the combination of US’426 modified by US’885, US’622, and US’819 do not disclose that the scFv that binds to PSMA is capable of binding to cynomolgus PSMA, the ability of an antibody to bind is a necessary property resulting from the CDRs of an antibody. As the anti-PSMA antibody of US’819 comprises the same CDRs as the antibodies demonstrated in the instant disclosure, the antibodies would naturally bind to cynomolgus PSMA.
Claim 34 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 14-34 of U.S. Patent No. US 11,352,426 B2 in view of US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017 and US 2018/0273622 A1 (Tan, P. and J.W. Blankenship) 27 SEP 2018 as applied above, and in further view of WO 2007/042261 (Kischel, R., et al) 19 APR 2007.
US’426 modified by US’885 and US’622 teaches the bispecific antibody of claim 1 as discussed in detail above.
The combination of applied references, however, does not disclose that the anti-CD3 scFv VH and VL comprises the claimed CDR sequences.
The teachings of WO’261 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the VH and VL in the anti-CD3 scFv in the bispecific antibody taught by US’426 modified by US’885 and US’622 with the anti-CD3 VH and VL of WO’261. An ordinarily skilled artisan would have been motivated to make this substitution in order to test cross-reactivity for use in preclinical evaluations of safety, activity, and/or pharmacokinetic profiling. An ordinarily skilled artisan would have had a reasonable expectation of success because the VH and VL of WO’261 binds to CD3, which is the same target as the scFv in US’426 modified by US’885 and US’622. Additionally, all of US’426, US’885, US’622, and WO’261 are teaching bispecific antibodies.
Claim 86 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 14-34 of U.S. Patent No. US 11,352,426 B2 in view of US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017 and US 2018/0273622 A1 (Tan, P. and J.W. Blankenship) 27 SEP 2018 as applied above, and in further view of US 2019/0135943 A1 (Boustany, L.M., et al) 09 MAY 2019 and US 2019/0022205 A1(Salih, H., et al) 24 JAN 2019.
US’426 modified by US’885 and US’622 is as discussed in detail above
The combination of applied references, however, does not disclose that the bispecific antibody is used in a method of detecting PSMA and CD3 as recited in instant claim 86.
The teachings of US’943 and US’205 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to use the bispecific antibody disclosed by US’426 modified by US’885 and US’622 in a method of detecting PSMA and CD3 in a sample as disclosed by US’943 and US’205. It would have been obvious to use the antibody to detect PSMA and CD3 in a sample as US’943 demonstrates that such methods for detecting bispecific antigen targets in a sample were known in the prior art. The use of the bispecific antibody to detect the antigens is further supported by US’205, which teaches that such methods can be used to detect or diagnose a disease. An ordinarily skilled artisan would have had a reasonable expectation of success as the applied references are all drawn to bispecific antibodies. Additionally, US’205 teaches detection methods using PSMA x CD3 bispecific antibodies, which are the same targets as the bispecific antibodies disclosed by US’426 modified by US’885 and US’622.
16/817,597
Claims 1-2, 27, 29, 31, 37, 42, 78-81, 85, 87-88, and 92-94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 154-159, 162, 164-166, and 169-174 of copending Application No. 16/817,597 in view of US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017 and US 2018/0273622 A1 (Tan, P. and J.W. Blankenship) 27 SEP 2018.
App’597 claims a polypeptide comprising, from amino to carboxyl-terminus, a first binding domain that specifically binds PSMA having LCDR 1-3 of SEQ ID NOs: 15-17, respectively, and HCDR 1-3 of SEQ ID NOs: 9-11, respectively, wherein the first binding domain is an scFv; a first hinge region; a first immunoglobulin constant region; and a second binding domain that specifically binds CD3. The PSMA CDRs of App’597 comprise those of instant claims 31 and 37. App’597 further claims a heterodimeric PSMA binding protein comprising the polypeptide and a second polypeptide comprising a binding domain that specifically binds human PSMA. App’597 claims an expression vector comprising the first and second expression units and a composition comprising the heterodimeric PSMA binding protein and a pharmaceutically acceptable carrier, diluent, or excipient. App’597 further claims a method of treating a cancer, prostate disorder, or neovascular disorder comprising administering the heterodimeric PSMA binding protein.
The claims of App’597 differ from the instantly claimed invention in that App’597 does not expressly state that the bispecific antibody does not contain a second CD3 binding domain or that the second polypeptide comprises an immunoglobulin constant region. App’597 also does not claim a method of producing the bispecific antibody.
The teachings of US’885 and US’622 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to produce the bispecific antibodies claimed in US’426 using two polypeptides with two scFv targeting the tumor associated antigen and a single scFv targeting CD3, as taught by US’885, where the bispecific antibody is formed using dimerization techniques as disclosed by US’885 and US’622. It would have been obvious to make this substitution as US’885 teaches multispecific binding molecules that have monovalent specificity for one target and bivalent specificity for the other. Additionally, US’885 demonstrates a multispecific binding peptide that has two PSMA binding region and a single CD3 binding region. An ordinarily skilled artisan would have had a reasonable expectation of success as US’885 demonstrates that such a format is capable of inducing cytotoxicity. Additionally, all of US’426, US’622, and US’885 are teaching bispecific binding molecules that target a tumor associated antigen and a T cell antigen, including PSMA or HER2 and CD3.
Regarding claim 27, while App’597 does not explicitly claim that the scFv that binds to PSMA is capable of binding to cynomolgus PSMA, the ability of an antibody to bind is a necessary property resulting from the CDRs of an antibody. As the anti-PSMA antibody of App’597 comprises the same CDRs as the antibodies demonstrated in the instant disclosure, the antibodies would naturally bind to cynomolgus PSMA.
Claim 34 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 154-159, 162, 164-166, and 169-174 of copending Application No. 16/817,597 in view of US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017 and US 2018/0273622 A1 (Tan, P. and J.W. Blankenship) 27 SEP 2018 as applied above, and in further view of WO 2007/042261 (Kischel, R., et al) 19 APR 2007.
App’597 modified by US’885 and US’622 teaches the bispecific antibody of claim 1 as discussed in detail above.
The combination of applied references, however, does not disclose that the anti-CD3 scFv VH and VL comprises the claimed CDR sequences.
The teachings of WO’261 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the VH and VL in the anti-CD3 scFv in the bispecific antibody taught by App’597 modified by US’885 and US’622 with the anti-CD3 VH and VL of WO’261. An ordinarily skilled artisan would have been motivated to make this substitution in order to test cross-reactivity for use in preclinical evaluations of safety, activity, and/or pharmacokinetic profiling. An ordinarily skilled artisan would have had a reasonable expectation of success because the VH and VL of WO’261 binds to CD3, which is the same target as the scFv in App’597 modified by US’885 and US’622. Additionally, all of App’597, US’885, US’622, and WO’261 are teaching bispecific antibodies.
Claim 86 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 154-159, 162, 164-166, and 169-174 of copending Application No. 16/817,597 in view of US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017 and US 2018/0273622 A1 (Tan, P. and J.W. Blankenship) 27 SEP 2018 as applied above, and in further view of US 2019/0135943 A1 (Boustany, L.M., et al) 09 MAY 2019 and US 2019/0022205 A1(Salih, H., et al) 24 JAN 2019.
App’597 modified by US’885 and US’622 is as discussed in detail above
The combination of applied references, however, does not disclose that the bispecific antibody is used in a method of detecting PSMA and CD3 as recited in instant claim 86.
The teachings of US’943 and US’205 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to use the bispecific antibody disclosed by App’597 modified by US’885 and US’622 in a method of detecting PSMA and CD3 in a sample as disclosed by US’943 and US’205. It would have been obvious to use the antibody to detect PSMA and CD3 in a sample as US’943 demonstrates that such methods for detecting bispecific antigen targets in a sample were known in the prior art. The use of the bispecific antibody to detect the antigens is further supported by US’205, which teaches that such methods can be used to detect or diagnose a disease. An ordinarily skilled artisan would have had a reasonable expectation of success as the applied references are all drawn to bispecific antibodies. Additionally, US’205 teaches detection methods using PSMA x CD3 bispecific antibodies, which are the same targets as the bispecific antibodies disclosed by App’597 modified by US’885 and US’622.
This is a provisional nonstatutory double patenting rejection.
Allowable Subject Matter
Claim 75 is objected to, but would be allowable if the objection is overcome.
Claim 76 is allowable.
The following is a statement of reasons for the indication of allowable subject matter: The instant claims are drawn to bispecific antibodies that bind PSMA and CD3 comprising the amino acid sequences recited. In searches of the prior art, no sequences were identified that match the binding domains of the claimed bispecific antibodies. Additionally, no reasonable expectation of success was identified in the art to modify known antibody binding regions arriving at the instantly claimed invention.
US 2018/0273622 A1 (Tan, P. and J.W. Blankenship) 27 SEP 2018 and US 2017/0089885 A1 (Blankenship, J., et al) 30 MAR 2017 are identified as the closest prior art and are discussed in detail in the 35 USC 103 rejections above. US’622 and US’885; however, do not disclose the VH and VL regions of scFvs in the instantly claimed bispecific antibodies.
WO 2012/145714 A2 (26 OCT 2012) teaches mono and multi-specific PSMA antibodies for the treatment of prostate cancer (abstract) and teaches a humanized anti-PSMA antibody, 107-1A4, with a VH and VL of SEQ ID NOs: 27 and 23 (page 34, [0127]), respectively. The sequences, aligned with instant SEQ ID NOs: 82 and 84, which are comprised in the ScFv of SEQ ID NO: 86 and SEQ ID NOs: 106, 178, and 112, are shown below:
WO’714 SEQ ID NO: 27 aligned with instant SEQ ID NO: 82
PNG
media_image8.png
235
618
media_image8.png
Greyscale
WO’714 SEQ ID NO: 23 aligned with instant SEQ ID NO: 84
PNG
media_image9.png
232
620
media_image9.png
Greyscale
As shown, both sequences comprise mismatches in the framework regions of the variable domains.
The instant specification details the humanization of PSMA-specific clone 107-1A4 in scFv format (Example 4) and discloses that the antibody was re-humanized in order to optimize all binding, functional, and manufacturing properties and performed in multiple stages (page 80, [00140]).
The prior art does not provide any reason to re-humanize the known VH and VL regions of the humanized 107-1A4 antibody nor does the art suggest the specific mutations in WO’714 SEQ ID NOs: 27 and 23 or that such mutations would have predictable results. Therefore, no reasonable expectation of success was identified that would have allowed an ordinarily skilled artisan to predictably modify the prior art sequences in order to arrive at the instantly claimed invention.
Conclusion
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693