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 .
Application Status
Claims 1-20 are pending and examined on the merits herein.
Specification
The disclosure is objected to because of the following informalities:
The reference to the sequence listing refers to the size in kb but it is required to be disclosed in bytes.
Appropriate correction is required.
The use of the term nanobody on page 14, Alexa fluor on page 74, Biacore on page 70, and Tween on page 68 which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 1, 8-9, 11-13, and 16-17 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.
Regarding claims 1, 8-9, 11-12, and 16-17 the phrase "preferably" or “more preferably” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 13, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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, 5, and 7-20 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 teachings of the specification and the claimed invention:
Claim 1 is directed to a genus of antibodies that bind to tau protein with an epitope within SEQ ID NO: 1, wherein the antibody thereof binds paired helical filament (PHF)-tau, that comprises one or more but not all of phosphorylated T427, S433 and S435.
Claims 7-17 and 19-20 depend from claim 1 without resolving the issue identified above.
Claim 5 allow heavy and light chain exchange for the PHF tau antibody.
Claim 5 allows combination of a first heavy chain of SEQ ID NO: 15 or 20, with 2 light chains having a SEQ ID NO: 16, 21, 24, or 60 and a second heavy of Seq ID NO: 17 or 22. This results in over 4000 possible combinations, but there are still only 4 embodiments generated.
Claim 18 allow heavy and light chain exchange for the PHF tau antibody as well as various scFv for the fusion construct. Claim 18 adds an additional 2 options of scFv to the combinations of claim 5 resulting in over 8000 total possibilities including the 4000 possible anti-PHF Tau, with 16 embodiments generated.
The instant specification does not define the structural features of the paratope-epitope binding and the residues therein that facilitate binding of an antibody tau protein with an epitope within SEQ ID NO: 1, wherein the antibody thereof binds paired helical filament (PHF)-tau, that comprises one or more but not all of phosphorylated T427, S433 and S435. Claims 1, 7-17, and 19-20, do not define the CDRs comprising the binding paratope of the antibody. The instant specification discloses a murine monoclonal antibody PT/66 that binds to Tau and is then humanized to form PTB1142 a Fab variant with three mutations at T427, S433 and S435; PT1B1153 the full human IgG version of PTB1142; PTB1153 with a modified light chain framework and another humanized antibody PT1B1183 (Example 1, page 68). Table 1 a further discloses humanized anti-Tau variants PT1B901, PT1B1153, PT1B635, and PT1B1183 with corresponding CDR; VH and VL; and HC and LC sequences (page 70). This table contains a listing of all of the matched pairs of VH/VL and HC/LC, but it is not comprehensive to the list of possible combinations as recited in the claims. Table 3 lists 16 Tau-BBB molecules that combine a TfR or CD98 scFv to the HC/LC anti-PHF Tau construct, again the list is not comprehensive to the possible combinations as claimed.
Epitope mapping was not done for any of the clones.
As detailed below the state of the art does not recognize that a person of ordinary skill in the art could envision a genus of antibodies defined by epitope or function.
The disclosed antibody clones are not representative of the claimed genus of antibodies. This is because when antibodies are raised to an antigen each monoclonal antibody raised comes from one unique cell with unique CDRs which are responsible for antibody binding, such that the structure of CDRs for one antibody cannot be considered representative of other antibodies with different CDRs that bind the same antigen or even substantially the same epitope. Notably, the epitope structure that one antibody binds on an antigen, do not inform the skilled artisan as to what other antibodies would bind the same or substantially the same structure.
Claim analysis:
Regarding claim 1 and dependent claims 7-17 and 19-20; as detailed below, one skilled in the art would be unable to envision the entire genus of antibodies that would bind to tau protein with an epitope within SEQ ID NO: 1, wherein the antibody thereof binds paired helical filament (PHF)-tau, that comprises one or more but not all of phosphorylated T427, S433 and S435.
Regarding claims 5 and 18, the instant disclosure does not test the possible combinations of the various HC/LC or VH/VL as recited in the claims outside of the clones presented in Tables 1 and 3 and therefore as detailed below applicant was not in possession of the entire range of combinations that maintain the ability to bind to PHF-Tau.
The state of the art as it applies to the claimed invention:
Regarding function claimed by epitope:
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Biodrugs (2007), 21 (3): 145-156; page 146, section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al. Protein Science (2005), 14:246–248; page 246). 3D structural analyses of antibody-epitope binding highlights the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al. J Comput Chem (2005), 26(9):879-87; page 879).
Ladner (Biotechnology and Genetic Engineering Reviews (2007), 24(1): 1-30) teaches that competitive binding assays demonstrate that two antibodies bind to overlapping or non-overlapping epitopes but not the same epitope (page 3; paragraph 3), so for accurate epitope mapping techniques that can be used are large energy transfer between labeled antibody to an antigen, antigen fragment binding, competitive peptide and antigen binding to antibody, antigen or antibody mutation, antigen-antibody complex analysis by NMR, determination of the 3D crystal structure of the antigen-antibody complex or electron microscopy (pages 5-7).
There are antibodies that bind to PHF-Tau known in the art. Mercken (US 2018/0265575 A1; PTO-892; corresponds to US10,766,953 B2; IDS entered 04/22/2024) teaches monoclonal anti-PHF-tau antibodies and antigen binding fragments thereof (abstract), wherein the antibody is a humanized monoclonal antibody (para 0012). Van Kolen (US 2019/0270793 A1; PTO-892 corresponds to US 10,633,435 B2; IDS entered 04/22/2024) teaches an isolated antibody or antigen-binding fragment thereof that binds to PHF-tau (claim 1; Fig 1). Singer (Biochem Biophys Res Commun. 2006 Aug 4;346(3):819-28; PTO-892) teaches 6 monoclonal antibodies generated against peptides including PHF-tau specific local phosphorylation patterns at Thr212/Ser214 and Thr231/Ser235, and 4 of these antibodies recognize PHF-tau without significant cross-reactivity towards normal human tau and dephosphorylated PHF-tau (abstract). Liu (J Neurosci. 2016 Dec 7;36(49):12425-12435; PTO-892) teaches active vaccination directed against phospho-tau (p-tau) peptides or passive immunization with specific high-affinity anti-tau monoclonal antibodies have both been shown to reduce tau pathology and to reduce behavioral deficits in mutant tau transgenic mice (page 12426, col 1, para 2) which would generate antibodies in vivo. Li (J Neurochem. 2020 Jan;152(1):122-135; PTO-892) teaches validation of specificity of numerous anti phospho tau antibodies that react with specific phosphorylation sites (Table 1). Hanger (Trends Mol Med, 2009, 15(3):112-9; IDS entered 4/22/2024) teaches that in tauopathies pathological tau is in an elevated state of phosphorylation (abstract and specifically identifies T427, S433 and S435 phosphorylation sites in the Alzheimer brain (Figure 1; Table 1). Wang (WO 2020/037311 A1; IDS entered 04/22/2024) teaches protein and peptide biomarkers for traumatic injury to the central nervous system (abstract) including Alzheimer’s disease (para 0074), including SEQ ID NO: 474 (claim 2) which has 100% sequence identity to the instant claimed SEQ ID NO: 1 and further that embodiments of the invention include a diagnostic kit comprising (a) detection agents for antibody, aptamer or mass spectrometry detection methods for detection of one or more peptide fragments selected from the group consisting of SEQ ID NO: 474 (para 0029). None of these antibodies specify binding to the phosphorylation sites instantly claimed.
Regarding chain swapping:
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
Accordingly, one skilled in the art would be unable to predict or envision a genus of antibodies that bind to tau protein with an epitope within SEQ ID NO: 1, wherein the antibody thereof binds paired helical filament (PHF)-tau, that comprises one or more but not all of phosphorylated T427, S433 and S435. Since the disclosure fails to describe a sufficient number of species to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Wang (WO 2020/037311 A1; IDS entered 04/22/2024) and Hanger (Trends Mol Med, 2009, 15(3):112-9; IDS entered 4/22/2024).
Regarding claim 1, Wang teaches protein and peptide biomarkers for traumatic injury to the central nervous system (abstract) including Alzheimer’s disease (para 0074). Wang further teaches a method of diagnosing trauma to the central nervous system in a subject in need thereof, comprising detection of a Tau-441 peptide fragment (claim 1) including SEQ ID NO: 474 (claim 2), which has 100% sequence identity to the instant claimed SEQ ID NO: 1. Wang further teaches that embodiments of the invention include a diagnostic kit comprising (a) detection agents for antibody, aptamer or mass spectrometry detection methods for detection of one or more peptide fragments selected from the group consisting of SEQ ID NO: 474 (claim 18). Wang further teaches that the primary antibodies specifically recognize and bind to a single peptide (para 0115).
Wang does not teach wherein the antibody or antigen binding fragment thereof binds a PHF-Tau with phosphorylation at one or more but not all of T427, S433 and S435.
Hanger teaches that in paired helical filaments (PHF) are the structural constituents of neurofibrillary tangles in Alzheimer’s disease and are composed of hyperphosphorylated forms of the microtubule associated protein tau (PHF-tau)(abstract). Hanger further teaches that in tauopathies pathological tau is in an elevated state of phosphorylation (abstract) and specifically identifies T427, S433 and S435 phosphorylation sites in the Alzheimer brain (Figure 1; Table 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to generate an antibody to a phosphorylated T427, S433 or S435 PHF-Tau as a marker of tauopathy as taught by Hanger in the diagnostic kit comprising antibodies to detect Alzheimer’s disease as taught by Wang. The ordinary artisan would have been motivated to do so because Hanger teaches that in tauopathies pathological tau is in an elevated state of phosphorylation and specifically identifies T427, S433 and S435 phosphorylation sites in the Alzheimer brain and Wang teaches protein and peptide biomarkers for traumatic injury to the central nervous system including Alzheimer’s disease as well as a diagnostic kit comprising antibodies for detecting the peptides.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claim(s) 7-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang (WO 2020/037311 A1; IDS entered 04/22/2024) and Hanger (Trends Mol Med, 2009, 15(3):112-9; IDS entered 4/22/2024) as applied to claim 1 above, and further in view of Terstappen (Nat Rev Drug Discov 20, 362–383 (2021); PTO-892).
The teachings of Wang and Hanger regarding claim 1 are detailed above.
Wang and Hangar do not teach a multispecific antibody that targets TfR or CD98.
Terstappen teaches that to get therapeutics across the blood brain barrier, ubiquitous targets such as CD98hc and transferrin (TfR) have been used to generate monospecific and multispecific antibodies (page 363, col 1, para 1). Terstappen further teaches that TfR is the most widely studied and independently validated target protein for receptor mediated transcytosis including antibodies, scFv, and DVD-Ig™ (page 363, col 1, para 2) some of which have already show promising results in clinical trials including an anti-amyloid beta fusion to an sFab targeting TfR (page 363, col 2, para 2). Terstappen further teaches that binding affinity of the antibody determines whether the antibody or antibody conjugated cargo can be efficiently transcytosed and released from the receptor at the abluminal side of the BBB: specifically that low- affinity binding of a bispecific antibody recognizing TfR and β- secretase 1 allowed more antibody molecules to be released from the receptors at the abluminal side of the BBB and that endosomal pH may affect the binding affinity of the TfR antibody for TfR, and low pH (pH 5.5) significantly increased transcytosis (Box 1, page 366).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add a TfR binding moiety to generate a multispecific antibody and optimize the binding kinetics as taught by Terstappen to the antibody to a phosphorylated T427, S433 or S435 PHF-Tau as taught by Wang and Hanger. The ordinary artisan would have been motivated to do so because Terstappen teaches that to get therapeutics across the blood brain barrier, ubiquitous targets such as CD98hc and TfR are used for receptor mediated transcytosis and further that there are clinical trials targeting amyloid beta and TfR in clinical trials. Terstappen further teaches that binding affinity of the antibody determines whether the antibody or antibody conjugated cargo can be efficiently transcytosed and released from the receptor at the abluminal side of the BBB: specifically that low- affinity binding of a bispecific antibody recognizing TfR and β- secretase 1 allowed more antibody molecules to be released from the receptors at the abluminal side of the BBB. The ordinary artisan has a reasonable expectation of success to generate a bispecific antibody targeting phosphorylated PHF-Tau and TfR with optimized binding kinetics that could be used as a diagnostic tool or therapeutic for Alzheimer’s disease.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
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, 19, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 10-11 of copending Application No. 18/552,504 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claim 1, the copending claims teach an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a tau protein at an epitope of the tau protein consisting of or within the amino acid sequence of SEQ ID NO: 1, wherein the antibody or antigen-binding fragment thereof binds paired helical filament (PHF)-tau, preferably human PHF-tau (claim 1), wherein (a) the epitope of the tau protein comprises either one of phosphorylated S433 or phosphorylated S435 of the tau protein, but does not comprise phosphorylated S433 and phosphorylated S435; (b)the epitope of the tau protein comprises one or more of phosphorylated T427, phosphorylated S433 and phosphorylated S435 of the tau protein, but does not comprise all of phosphorylated T427, phosphorylated S433 and phosphorylated S435; (c) the epitope of the tau protein comprises one or more of phosphorylated T427 and phosphorylated S433 of the tau protein, but does not comprise phosphorylated S435, and does not comprise all of phosphorylated T427, phosphorylated S433 and phosphorylated S435; or (d) the epitope of the tau protein comprises phosphorylated T427 of the tau protein, but does not comprise phosphorylated S433 or phosphorylated S435 (claim 2).
Regarding claim 19, the copending claims teach an isolated nucleic acid encoding the isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 (claim 10).
Regarding claim 20, the copending claims teach a vector comprising the isolated nucleic acid of claim 10 (claim 11).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 7-14, 16-17, and 19-20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-6, and 8-15 of copending Application No. 18/846,151 and 18/846,170 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The rejections for these copending applications are combined as they are statutory duplicates of each other.
Regarding claims 1-2 and 7-10, the copending claims teach a multispecific antibody or antigen binding fragment thereof comprising a first antigen-binding region capable of binding specifically to pyroglutamate amyloid-β, a second antigen-binding region capable of binding specifically to transferrin receptor (TfR), and a third antigen-binding region capable of binding specifically to paired helical filament (PHF)-tau, wherein: a. the first antigen-binding region comprises: i. a first heavy chain variable region (VH1) comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 8 or 16, 9 or 17, and 10, respectively; and ii. a first light chain variable region (VL1) comprising light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; b. the second antigen-binding region comprises: i. a second heavy chain variable region (VH2) comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and ii. a second light chain variable region (VL2) comprising light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; and c. the third antigen-binding region comprises: i. a third heavy chain variable region (VH3) comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs:28, 29, and 30, respectively; and ii. a third light chain variable region (VL3) comprising light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs:31, 32, and 33, respectively (claim 1). SEQ ID NO: 28-33 have 100% sequence identity to the instant claimed SEQ ID NO: 4-9. SEQ ID NO: 1-6 have 100% sequence identity to the instant claimed SEQ ID NO: 35-40. The same CDRs for anti-TfR antibody would result in the same binding kinetics.
Regarding claim 2, the copending claims further teach a multispecific antibody or antigen binding fragment thereof comprising a first heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO:24, and a first light chain comprising an amino acid sequence at least 90% identical to SEQ ID: NO:25, and a second heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO:26 (claims 12-13). SEQ ID NO: 24 has over 98% sequence identity to instant claimed SEQ ID NO: 18 and 19.
Regarding claim 11, the copending claims teach the multispecific antibody or antigen binding fragment thereof of claim 1, wherein the second antigen-binding region comprises a single chain fragment variable (scFv) antibody or antigen binding fragment thereof comprising the VH2 and VL2 (claim 4), wherein the scFv comprises an amino acid sequence at least 90% identical to SEQ ID NO:7 (claims 5-6), SEQ ID NO: 7 has 100% sequence identity to instant claimed SEQ ID NO: 34.
Regarding claim 12, the copending claims teach wherein the scFv is linked to the carboxy terminus of the first heavy chain constant region via a linker, more particularly a linker comprising the amino acid sequence of SEQ ID NO:27 (claim 8).
Regarding claims 13-14, the copending claims teach wherein the Fc1 and Fc2 each comprise one or more heterodimeric mutations, such as a first and a second modified heterodimeric CH3 domains, respectively, as compared to a wild-type Fe region; particularly, the Fc1 comprises amino acid modifications at positions T350, L351, F405, and Y407, and the Fc2 comprises amino acid modifications at positions T350, T366, K392 and T394, wherein the amino acid modification at position T350 is T350V, T3501, T350L or T350M; the amino acid modification at position L351 is L351 Y; the amino acid modification at position F405 is F405A, F405V, F405T or F405S; the amino acid modification at position Y407 is Y407V, Y407A or Y4071; the amino acid modification at position T366 is T366L, T3661, T366V or T366M, the amino acid modification at position K392 is K392F, K392L or K392M, and the amino acid modification at position T394 is T394W, and wherein the numbering of amino acid residues is according to the EU index as set forth in Kabat, more particularly, the Fc1 comprises amino acid modifications T350V, L351 Y, F405A and Y407V, and the Fc2 comprises amino acid modifications T350V, T366L, K392L and T394W (claim 9).
Regarding claim 16, the copending claims teach wherein at least one of the Fc1 and Fc2 comprises one or more mutations that enhance binding of the multispecific antibody or antigen binding fragment thereof to the neonatal Fe receptor (FcRn), preferably the one or more mutations enhance the binding at an acidic pH, more preferably the at least one of the Fc1 and Fc2 has the M252Y /S254T/T256E (YTE) mutations, wherein the numbering of amino acid residues is according to the EU index as set forth in Kabat (claim 10).
Regarding claim 17, the copending claims teach wherein at least one of the Fc1 and Fc2 comprises one or more mutations that reduce or eliminate the effector function, preferably the at least one of the Fc1 and Fc2 has one or more amino acid modifications at positions L234, L235, D270, N297, E318, K320, K322, P331, and P329, such as one, two or three mutations of L234A, L235A and P331S, wherein the numbering of amino acid residues is according to the EU index as set forth in Kabat (claim 11).
Regarding claim 19, the copending claims teach an isolated nucleic acid sequence encoding the multispecific antibody or antigen binding fragment thereof of claim 1 (claim 14).
Regarding claim 20, the copending claims teach a vector comprising the isolated nucleic acid of claim 14 (claim 15).
The instant claims do not teach a trispecific antibody comprising a binding site targeting pyroglutamate amyloid beta.
It would be obvious to the ordinary artisan to generate a bispecific antibody to target PHF-Tau and TfR with the binding moieties from the trispecific antibody. This is obvious from the previous art establighing bispecifics with Alzheimer’s targets and TfR to cross the BBB. See the teachings of Terstappen (Nat Rev Drug Discov 20, 362–383 (2021); PTO-892) below.
Terstappen teaches that to get therapeutics across the blood brain barrier, ubiquitous targets such as CD98hc and transferrin (TfR) have been used to generate monospecific and multispecific antibodies (page 363, col 1, para 1). Terstappen further teaches that TfR is the most widely studied and independently validated target protein for receptor mediated transcytosis including antibodies, scFv, and DVD-Ig™ (page 363, col 1, para 2) some of which have already show promising results in clinical trials including an anti-amyloid beta fusion to an sFab targeting TfR (page 363, col 2, para 2). Terstappen further teaches that binding affinity of the antibody determines whether the antibody or antibody conjugated cargo can be efficiently transcytosed and released from the receptor at the abluminal side of the BBB: specifically that low- affinity binding of a bispecific antibody recognizing TfR and β- secretase 1 allowed more antibody molecules to be released from the receptors at the abluminal side of the BBB and that endosomal pH may affect the binding affinity of the TfR antibody for TfR, and low pH (pH 5.5) significantly increased transcytosis (Box 1, page 366).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Allowable Subject Matter
Claims 3-4 and 6 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643