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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 07-29-2026 is acknowledged.
Claims 1-51 are pending.
Claims 28-40, and 45-50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-27, 41-44, and 51 are pending and are currently under consideration.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See for example, page 82, line 4. Applicant is required to delete any and all embedded hyperlinks and/or other forms of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 8-9 are objected to for reciting amino acid sequences (e.g., X1YYX2H, VX₁IVVLRSTPTLYYX₂DY) in the absence of respective sequence identifiers. See 37 CFR 1.821(c). 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-24, and 42-44 rejected under 35 U.S.C. 101 because the claimed invention is directed to natural products without significantly more.
The claims are broadly drawn to antibodies that bind to a phosphorylated C-terminal domain or fragment of TAR-DNA-binding protein 43 (TDP-43) wherein the serine residues at positions 403 and/or 404 are phosphorylated. The specification teaches [0005] that with the seminal discovery that the RNA binding protein TDP-43 as a major component of the cytoplasmic ubiquitinated inclusions found in sporadic ALS and FTLD patients, researchers obtained, for the first time, a handle with which to investigate sporadic disease. While TDP-43 is arguably the most important molecular target for ALS and FTLD therapy, its essential cellular functions preclude therapeutic strategies [0006]; however, an increasing number of reports suggest that TDP-43 can behave in a prion-like manner, both in in vitro and in vivo experimental systems [0008]. Regarding antibodies, the specification teaches [0190] that the present inventors surprisingly identified human antibodies, which specifically bind to pathological, but not to physiological (non-pathological), TDP-43 with high affinity. In particular, these antibodies (specifically) bind to a phosphorylated C-terminal domain or fragment of TAR-DNA-binding protein 43 kDa (TDP-43; SEQ ID NO: 1) comprising amino acids 391-414 of SEQ ID NO: 1, wherein the serine residues at positions 403 and 404 of SEQ ID NO: 1 are phosphorylated. The specification further teaches [0602] that to detect individuals harboring antibodies directed against pTDP-43 peptides, a large unselected population, with a clinical history unknown at the time of conducting the test, was screened for seroreactivity to pTDP-43 peptides in a high-throughput ELISA. These natural, human antibodies were subsequently cloned [0611] and corrected for any sequence mismatches in the Ig-variable regions [0613]. The CDR and VH/VL sequences of the exemplified and natural antibodies are shown on page 61 of the specification. These domains are also inclusive of the claimed CDRs and VH/VL in claims 8-17.
Thus, the claimed antibodies are not sufficiently distinguishable from the anti-TDG-43 antibodies as they exist naturally because the claims do not particularly point out any non-naturally occurring differences between the claimed products and the naturally occurring products. For example, many of the dependent claims are limited to functional features (e.g., Claim 3- “wherein the antibody or the antigen-binding fragment does not bind to non-pathological TDP-43”, Claim 4- “wherein the antibody or the antigen-binding fragment binds to high-molecular weight aggregates of TDP-43”, Claim 5- “wherein the antibody or the antigen-binding fragment binds to C-terminal fragments of TDP-43”) which are naturally occurring biological functions undistinguishable from the pool of naturally occurring anti-TDP-43 antibodies. When a law of nature or natural phenomenon is claimed as a physical product, the courts have often referred to the exception as a "product of nature". For example, the isolated DNA of Myriad and the primers of Ambry Genetics were described as products of nature by the courts. Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 580, 106 USPQ2d 1972, 1975 (2013); University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 758-59, 113 USPQ2d 1241, 1243 (Fed. Cir. 2014). As explained in those decisions, products of nature are considered to be an exception because they tie up the use of naturally occurring things, but they have been labeled as both laws of nature and natural phenomena. See MPEP 2106.04(b). In contrast, the structural variants of antibodies represented by claims 25-27 are produced artificially. Claim 24 is included in this rejection because single-chain antibodies are inclusive of naturally occurring single-domain antibodies present in llamas and camels, and such higher eukaryotic organisms contain the TARDBP gene.
Further, the human intervention required by claims 23, and 42-44 is limited to isolating the natural antibody products and forming compositions with generic excipients, or diluents or carriers. However, these additional elements do not add more than insignificant extra-solution activity to the judicial exception. As explained by the Supreme Court, the addition of insignificant extra-solution activity does not amount to an inventive concept, particularly when the activity is well-understood or conventional. Parker v. Flook, 437 U.S. 584, 588-89, 198 USPQ 193, 196 (1978). See MPEP 2106.05(g).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-9, 12-14, 17-27, 41-44, and 51 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. This is a Written Description Rejection.
The claims are broadly drawn to a genus of antibodies. For example, Claim 1 comprises any antibody or antigen binding fragment thereof that bind to TDP-43 wherein the serine residues at positions 403 and/or 404 are phosphorylated. Similarly, claim 3-7 are drawn to the same genus of antibodies as claim 1, but with different functional activities, such as “binds to high-molecular weight aggregates of TDP-43” or “decreases TDP-43 aggregation”.
The specification teaches (page 61 and 110) a written description of antibodies defined by structure and referred to as 31F3, 30E1, 95LL and 15D7. For example, the 31F3 antibody has a variable heavy domain comprising SEQ ID NO:9 and a variable light domain comprising SEQ ID NO:10. The specification further teaches (page 111-112, example 2) that these antibodies are specific to pathological TDP-43 phosphorylated at positions S403 and S404. For non-pathological full-length TDP-43 and for TDP-43 phosphorylated at positions S409 and S410 no binding could be detected, indicating the high specificity and selectivity of the antibodies for pTDP-43 (403/404). However, the disclosure of 4 species of antibodies does not provide sufficient evidence of possession to the full genus of claimed antibodies. A "representative number of species" means that the species which are adequately described are representative of the entire genus. The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, inventor was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991). An applicant shows that the inventor was in possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties). Thus, the written description is not commensurate in scope with antibodies only defined by function such as thus presented in Claims 1-7 or those that purely limit the genus of claimed antibodies to generic fragments (e.g. single chain antibodies, Fabs, Fv) and generic compositions (e.g., purified compositions, kits, etc) such as those presented in claims 18-27, 41-44, and 51. Further, regarding the serine residues in Claim 1, all claims include a second genus of antibodies that specifically recognize TDP-43 wherein the serine residues can be phosphorylated at positions 403 or 404 while the specification only indicates binding when both serine residues are phosphorylated (Example 2).
Claims 8-9 further limit the genus of antibodies of claim 1 to structural variants of complementary determining regions (CDRs). For example, a CDRH1 is defined as X1YYX2H where X1 and X2 “may be any amino acid” and a CDRL2 is defined as EX1X2X3RPS where X1, X2, and X3 “may be any amino acid”. This amounts to at least 400 different CDRH1s and 8000 different CDRL2s not including the different combinations which could be formed. Further, claims 12-14 each depend from claim 1 and include at least 30% structural variability to the heavy and light chains of defined SEQ ID NOs. Claim 17 is dependent from Claim 1 and defines the heavy chains as any one of SEQ ID Nos: 9, 11, and 113 and the light chains as any one of SEQ ID Nos: 10, 112, or 114. All of these structural variants are also not commensurate in scope to the claimed genus of antibodies that bind to TDP-43 wherein the serine residues are phosphorylated at positions 403 and/or 404.
Sela-Culang, Kunik, and Ofran (Fron. Immuno., Vol. 4, Article 302, Oct. 2013), hereinafter “Sela-Culang”, reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies typically consists of four polypeptide chains with two identical heavy (H) and two identical light (L) chains, with H and L chains liked to form a Y-shaped structure known as a Fab [e.g., pg. 4, Figure 2A-B]. The Fab has two variable (V) domains (VH and VL) that dimerize to form the Fv fragment which comprises the antigen-binding site of the antibody via six hypervariable loops (3 Heavy, 3 light) [e.g., pg. 3, “The Role of CDRs and their Definition”]. The six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition [e.g., pg. 1, abstract] and the three-dimensional configuration of these CDRs form the antigen-recognition complex termed a paratope [e.g., pg. 3, “The Role of CDRs and their Definition”]. Despite the integrated effect of CDRs, antibodies can also be considered a modular system, composed of different elements (e.g., Fab, VH, VL) which may bind to an antigen on their own with the smaller fragments retaining affinity and specificity, which is of great potential for drug design [e.g., pg. 6, paragraph 2]. A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized [e.g., pg. 1, “The Motivations for…”].
Further, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017), hereinafter “Herold”, teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” [e.g., pg. 14, paragraph 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, paragraph 3]. Herold further teaches that variable heavy chain (VH) mutations led to a decrease in binding affinity, with as much as 20-fold higher KD in the mutant versus wild type [e.g., pg. 4, paragraph 3], and summarizes the antigen binding KD differences based on point mutations in the VH or VL of an IgG antibody [e.g., pg. 6, table 1].
As further evidence, see Koenig et al. (PNAS, E486-E4995, January 5, 2017), which provides a large mutation analysis study where every amino acid in both variable regions are substituted with every other amino acid. In review of figure 1, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, with blue meaning a reduced affinity and black meaning complete loss of binding ability. In VL-CDR1, for example, mutating any given residue to cysteine, which is encompassed by the instant claims (undefined sequence variability up to 3 amino acids or 5% sequence identity, depending on the claim language), resulted in reduced binding at 7 residues and a complete loss of binding (no longer binds same target) at 4 residues. That is, at 100% of positions, mutation to cysteine reduced or ablated the antibody’s ability to bind the target, even in the case of conservative mutations.
Thus, making changes to the CDR sequence of an antibody sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
As indicated by the art, a full complement of 6 CDRs are required for antigen binding and one cannot predict which CDR residues may be changed and still result in an antibody that binds PD-L1 and E3 ligase at the claimed epitope(s). Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 6 CDRs in an antibody are the minimal structure that binds to a target antigen.
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.
Claim 8 is 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.
Regarding claim 8, the phrases "preferably," or “more preferably” or “even more preferably” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are actually part of the claimed invention. As such, these phrases create ambiguity as to whether or not the alternatives are distinct limitations. See MPEP § 2173.05(d).
No claim is currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643
