DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment, filed 09/26/2023, has been entered.
Claims 1, 48-68 are pending.
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 01/12/2026 is acknowledged. The traversal is on the ground(s) that examining Groups I and II together would not present an undue burden. This is not found persuasive for reasons stated in the Restriction Requirement, mailed 12/31/2025. Groups I-IV lack unity of invention because the groups do not share the same or corresponding technical feature. Where the claims of Groups III and IV are directed to methods of using the antibody, whereas the claims of Group Il are directed to a polynucleotide, a vector and a host cell, and thus the groups do not share a technical feature. As such, unity does not exist.
The requirement is still deemed proper and is therefore made FINAL.
Claims 52-54 and 57-68 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Inventions, there being no allowable generic or linking claim.
Claims 1, 48-51 and 55-56 are currently under examination as they read on an isolated antibody that binds to a cis conformation of a phosphorylated Threonine231-Proline (pThr231-Pro) motif of phosphorylated-Threonin231-tau protein (pThr231-tau).
Independent Claim
Claim 1. (Original) An isolated antibody or an antigen-binding fragment thereof comprising:
a complementarity-determining region (CDR) light chain 1 (CDR-L1) having the amino acid sequence of SEQ ID NO: 1 or a variant thereof; a complementarity-determining region (CDR) light chain 2 (CDR-L2) having the amino acid sequence of SEQ ID NO: 2 or a variant thereof; and/or a complementarity-determining. region (CDR) light chain 3 (CDR-L3) having the amino acid sequence of SEQ ID NO: 3 or a variant thereof; and/or
a complementarity-determining region (CDR) heavy chain 1 (CDR-H1) having the amino acid sequence of SEQ ID NO: 4 or a variant thereof; a complementarity-determining region (CDR) heavy chain 2 (CDR-H2) having the amino acid sequence of SEQ ID NO: 5 or a variant thereof; and/or a complementarity-determining region (CDR) heavy chain 3 (CDR-H3) having the amino acid sequence of SEQ ID NO: 6 or a variant thereof,
wherein a variant of a CDR comprises between 1 and 5 of any combination of amino acid substitutions, deletions, or additions;
wherein the antibody or antigen-binding fragment thereof is a humanized antibody or antigen binding fragment thereof;
and wherein
(A) the light chain variable domain comprises:
(i) a serine residue seventeen amino acid residues N-terminal to the CDR- L1; and/or
(B) the heavy chain variable domain comprises:
(i) a valine residue twenty-six amino acid residues N-terminal to the CDR- H1;
(ii) a serine residue twenty-four amino acid residues N-terminal to the CDR- H1;
(iii) a lysine residue nineteen amino acid residues N-terminal to the CDR-H1;
(iv) an arginine residue at the amino acid residue directly C-terminal to CDR- H2; and/or
(v) a valine residue seven amino residues C-terminal to CDR-H3.
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 49-51 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.
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, claims 49-51 recite narrower “optionally” limitations that are preceded by broader limitations. For example, claim 49 recites the broad recitation “the antibody or antigen-binding fragment thereof further comprises a threonine residue directly N-terminal to CDR-H3”, and the claim also recites “optionally, wherein the CDR-H3 and the amino acid residue directly N- terminal to CDR-H3 together comprise the amino acid sequence of SEQ ID NO: 13” is the narrower statement of the range/limitation.
The claims 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. Therefore, the metes and bounds of the claim are ambiguous and ill-defined.
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 1, 48-50 and 55-56 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The following grounds of rejection are set forth for not reciting an antigen specificity in the present claims.
Antibodies are glycoproteins that possess the ability to react in vitro and in vivo specifically and selectively with the antigenic determinants or epitopes eliciting their production or with an antigenic determinant closely related to the homologous antigen.
Antibodies are immunoglobulins that are formed in response to immunogens or that are screened for specificity an antigen / immunogen.
It has been well established in the art that the antigen binding specificity is critical to how the skilled artisan would employ antibodies in various modalities (e.g., affinity purification, detection or diagnostic assays, bioassays, treatment), including those consistent with the instant disclosure (see specification, including the Summary of the Invention).
The instant specification disclosed antibodies that bind specifically pThr231-Pro motif of pThr231-tau protein. However, the instant claims do not recite an antigen specificity.
The specification provides insufficient direction or guidance regarding how to make and use antibodies in the absence of an antigen specificity for pThr231-Pro motif of pThr231-tau protein, and yet retain substantially the same binding specificity of pThr231-Pro motif of pThr231-tau protein, which are enabling consistent with the disclosed utilities of the instant disclosure such as binding to pThr231-Pro motif of pThr231-tau protein, for example (see, e.g., Detailed Description).
Given the well-known polymorphism of antibodies, it would have been undue experimentation to make and use the vast repertoire of antibodies encompassed by the claimed invention in the absence of binding specificity to enable the scope of the claimed antibodies encompassed by the claimed invention.
Without sufficient guidance and given the well-known complexity and unpredictability of using antibodies with no particular antigen specificity as well the well-known polymorphism of antibodies; it would be unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue to make and use the vast repertoire of antibodies broadly encompassed by the claimed invention in order to make and use the antibodies consistent with the instant disclosure.
Applicant is invited to amend the claims by reciting the antigen-specificity, e.g., pThr231-Pro motif of pThr231-tau protein, in order to obviate this rejection.
Claims 1, 48-51 and 55-56 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.
The present claims are directed to an antibody that binds a cis conformation of a pThr231-Pro motif of pThr231-tau protein. The breadth of the claims encompasses a genus of antibodies that pThr231-Pro motif of pThr231-tau protein encompassing variants with substitutions, deletions or additions in CDR sequences, or variants with either the heavy or light chain CDRs defined. The present claims do NOT satisfy the written description requirement for the claimed genus for the following reasons:
The written description requirement for a claimed genus/subgenus may be satisfied through description of 1) a representative number of species OR 2) disclosure of relevant identifying characteristics, i.e., functional characteristics coupled with a known or disclosed correlation between function and structure.
Representative Species
With regard to representative number of species, the instant specification disclosed a number of species of the genus (pages 49-57). However, the disclosed species are not sufficient to represent the entire genus as claimed.
A “representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The “structural features common to the members of the genus” needed for one of skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural “stepping stone” to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The size of the claimed antibody genus comprises substantial variations as one of skill in the art is well aware of the high level of polymorphism and complex nature of immunoglobulins. Schroeder et al. taught that through somatic variation, combinatorial rearrangement of individual gene segments and combinatorial association between different L and H chains, the repertoire of antibody diversity can have greater than 1016 different immunoglobulins (J Allergy Clin Immunol 2010, 125:S41-S52).
Moreover, it is well-known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope. For example, Lloyd et al. taught that over hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Therefore, the disclosed species are not representative of the claimed genus encompassing the substantial variation due to the high level of polymorphism of antibodies as exemplified by the above references.
Structure-function correlation
Written description can also be satisfied with disclosure of relevant identifying characteristics, i.e., functional characteristics coupled with a known or disclosed correlation between function and structure. While the term “antibody” does impart some structure, the structure that is common to antibodies is generally unrelated to antigen-binding function because antibody CDRs are necessary for binding and they are highly diverse in structure and their sequence does not correlate to binding in a predictable fashion. The subgenus as recited in claim 30 encompasses more than 220,000 possible variants with substitutions in the CDRs. The Applicant does not have possession of all these variants as not all of them will have the binding function as required by the claims.
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs (or hypervariable regions), which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA 1982 Vol 79 page 1979). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. MacCallum et al. (J. Mol. Biol. 1996 262, 732-745), analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). Pascalis et al. (The Journal of Immunology (2002) 169, 3076-3084) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (BBRC 2003, 307:198-205), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.). Vajdos et al. (J. Mol. Biol. (2002) 320, 415-428), additionally state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.). Chen et al. (J. Mol. Bio. (1999) 293, 865-881) describe high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). Wu et al. (J. Mol. Biol. (1999) 294, 151-162) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation. Padlan et al. (PNAS 1989, 86:5938-5942) described the crystal structure of an antibody-lysozyme complex where all 6 CDRs contribute at least one residue to binding and one residue in the framework is also in contact with antigen. In addition, Lamminmaki et al. (JBC 2001, 276:36687-36694) describe the crystal structure of an anti-estradiol antibody in complex with estradiol where, although CDR3 of VH plays a prominent roll, all CDRs in the light chain make direct contact with antigen (even CDR2 of VL, which is rarely directly involved in hapten binding). Recently, studies have shown that changing in CDRs even alter Fc binding to the Fc receptor and pharmacokinetics (Piche-Nicholas et al. MABS 2018, 10:81-94).
Given the highly diverse nature of antibodies, particularly in the CDRs, by claiming a genus of antibodies defined by the antigen specificity without any defined structure/sequences is analogous to searching for a key “on a ring with a million keys on it” Centocor, 636 F.3d at 1352. Therefore, the claims do not satisfy the written description requirement as the structure-function correlation of the claimed subgenus not sufficiently described.
Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of antibodies that bind pThr231-Pro motif of pThr231-tau protein encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 48-51 and 55-56 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Kumar et al. (WO 2019/094595; see entire document).
Kumar et al. taught a conformation-specific antibody that specifically binds pT231-tau protein that has the same VH and VL CDRs as shown in the sequence alignment below (see, e.g., Summary paragraphs 0006-0009). Given that the antibody has the same CDRs, it would bind specifically to the cis conformation of pThr231-Pro motif of pThr231-tau protein. Moreover, Kumar taught CDR-L having the same sequence as SEQ ID NO: 7 and a framework region N-terminal to CDR-L1 having the sequence of SEQ ID NO: 36 (see paragraph 0171, SEQ ID NO: 42 of Kumar). Furthermore, Kumar taught a pharmaceutical composition comprising the antibody and a pharmaceutical acceptable carrier and a kit comprising the antibody (see paragraphs 0295 and 0307-0310).
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Claims 1, 49, 51, 55 and 56 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Lu et al. (US Patent 9,688,747; cited in IDS; see entire document).
Lu et al. taught a conformation-specific antibody that specifically binds pT231-tau protein that has the same VH and VL CDRs as shown in the sequence alignment below (see column 16, line 38 to column 17, line 3). Given that the antibody has the same CDRs, it would bind specifically to the cis conformation of pThr231-Pro motif of pThr231-tau protein. Moreover, Lu taught CDR-L having the same sequence as SEQ ID NO: 7 (see column 16, line 38 to column 17, line 3). Furthermore, Lu taught a pharmaceutical composition comprising the antibody and a pharmaceutical acceptable carrier and a kit comprising the antibody (see column 3 line 16 and column 31 line 33).
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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.
Claims 1, 49, 51, 55 and 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 14 of U.S. Patent No. 9,688,747. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims disclosed a conformational-specific antibody that binds cis conformation of pT231-tau and has the same CDR sequences as the presently claimed antibody (see discussion and sequence alignment above in 102). Therefore, the patent claims anticipate the present claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHARON X WEN whose telephone number is (571)270-3064. The examiner can normally be reached Mon-Fri 8-5.
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/SHARON X WEN/Primary Examiner, Art Unit 1641