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 the invention of Group I, drawn to an anti-transferrin receptor (TfR) antibody, in the reply filed on 05/18/2026 is acknowledged.
Applicant further elects an anti-TfR antibody wherein 1) the HCDR1 comprises SEQ ID NO: 1, the HCDR2 comprises SEQ ID NO: 10, the HCDR3 comprises SEQ ID NO: 11, the LCDR1 comprises SEQ ID NO: 9, the LCDR2 comprises SEQ ID NO: 5, and the LCDR3 comprises SEQ ID NO: 12; 2) the VH comprises SEQ ID NO: 32 and VL comprises SEQ ID NO: 33; and 3) the HC comprises SEQ ID NO: 58 and the LC comprises SEQ ID NO: 59. In addition, Applicant elects the following complete heavy and light chain pair for a single anti-TfR binding domain species: the HC1 comprises SEQ ID NO: 68, the LC1 comprises SEQ ID NO: 59, and the HC2 comprises SEQ ID NO: 69. Applicant also indicates that a half-life extender is present and elects an immunoglobulin Fc region. Lastly, Applicant indicates that the anti-transferrin binding protein is not a heterodimeric antibody comprising a TfR binding domain and a second null arm. Applicant states that claims 1-15 read on the elected species. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 16-120 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species or invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/18/2026.
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.
Written Description
Claims 1 and 4-13 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.
Claim 1 encompasses anti-TfR antibodies comprising light and heavy chain CDR sequences having Xaa residues that can be substituted by the different amino acids for a given position (see Sequence Listing). Given the number of combinations possible, claim 1 encompasses numerous antibody variants; yet the specification only discloses only a limited number of antibody sequences with confirmed human TfR binding (see Tables 1-3) and provides no evidence demonstrating that antibodies having different combinations of CDR substitutions encompassed by the claim 1 retain the ability to bind human TfR.
Claims 4-13 incorporate limitations of claim 1 but do not cure the deficiencies of claim 1 and thus are also rejected.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (MPEP 2163).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting at 1171, 25 USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
Claim 1 encompasses anti-TfR antibodies comprising light and heavy chain CDR sequences having Xaa residues that can be substituted by the different amino acids for a given position (see Sequence Listing). Given the number of combinations possible, claim 1 encompasses numerous antibody variants; yet the specification only discloses only a limited number of antibody sequences with confirmed human TfR binding (see Tables 1-3) and provides no evidence demonstrating that antibodies having different combinations of CDR substitutions encompassed by the claim 1 retain the ability to bind human TfR.
The specification teaches that antibody against human TfR was generated by immunized transgenic mice with apical domain of human TfR1 protein. Affinity variants of the human TfR antibodies were then generated by systematically introducing mutations into individual CDRs and the resulting variants were subjected to multiple rounds of selection to isolate clones with improved affinities. The sequences of individual variants were then used to construct a combinatorial library which was subjected to an additional round of selection with increased stringency to identify additive or synergistic mutational pairings between the individual CDR regions. Individual combinatorial clones were sequences as disclosed in Tables 1-3 (Example 1, Para. 000224-000227). As presently written, however, claim 1 encompasses anti-TfR antibodies comprising light and heavy chain CDR sequences having Xaa residues that can be substituted by the different amino acids for a given position (see Sequence Listing). Given the number of combinations possible, claim 1 encompasses numerous antibody variants; yet the specification only discloses only a limited number of antibody sequences with confirmed human TfR binding (see Tables 1-3) and provides no evidence demonstrating that antibodies having different combinations of CDR substitutions encompassed by the claim 1 retain the ability to bind human TfR. Further, the specification does not provide any guidance for predicting which combinations of light and heavy chain CDR substitutions would retain binding activity across the claim scope.
Therefore, the claimed genus of anti-human TfR antibodies lacks adequate written description because there does not appear to be any correlation between the structure of the claimed antibodies and the function of binding to human TfR. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of anti-human TfR antibodies at the time the instant application was filed.
Scope of Enablement
Claims 1 and 4-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for anti-human TfR antibodies having the particular CDR substitution combinations expressly disclosed and demonstrated to retain binding to human TfR, does not reasonably provide enablement for the genus of antibodies having numerous additional combinations of possible CDR substitutions for which the specification neither discloses nor provides evidence of human TfR binding. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The nature of the invention relates to anti-transferrin receptor (TfR) antibodies or conjugates thereof and their use in the treatment of CNS diseases (see Summary of Invention).
Claim 1 is broadly drawn to a protein comprising one monovalent human TfR binding domain, wherein the CDR from multiple structurally distinct VHH clones can be interchanged. Thus, the claim encompasses numerous possible CDR combinations beyond the specific parental clones and variants disclosed in the specification.
The specification teaches that antibody against human TfR was generated by immunized transgenic mice with apical domain of human TfR1 protein. Affinity variants of the human TfR antibodies were then generated by systematically introducing mutations into individual CDRs and the resulting variants were subjected to multiple rounds of selection to isolate clones with improved affinities. The sequences of individual variants were then used to construct a combinatorial library which was subjected to an additional round of selection with increased stringency to identify additive or synergistic mutational pairings between the individual CDR regions. Individual combinatorial clones were sequences as disclosed in Tables 1-3 (Example 1, Para. 000224-000227). As presently written, however, claim 1 encompasses anti-TfR antibodies comprising light and heavy chain CDR sequences having Xaa residues that can be substituted by the different amino acids for a given position (see Sequence Listing). Given the number of combinations possible, claim 1 encompasses numerous antibody variants; yet the specification only discloses only a limited number of antibody sequences with confirmed human TfR binding (see Tables 1-3) and provides no evidence demonstrating that antibodies having different combinations of CDR substitutions encompassed by the claim 1 retain the ability to bind human TfR. Further, the specification does not provide any guidance for predicting which combinations of light and heavy chain CDR substitutions would retain binding activity across the claim scope.
It is well-known in the art that amino acid variations in the CDRs of an antigen binding region can negatively impact binding activity (see, e.g. Piche-Nicholas et al, see in particular, Abstract; Colman, see entire document particularly Page 33, Col. 2; and Rudikoff et al, see Abstract). As such, artisans would not be able to readily predict which combination of light and heavy chain CDR substitutions can be made such that the resulting antibody retains the ability to bind to human TfR.
A person of ordinary skill in the art at the time of filing would have had experience in antibody engineering, including library construction, mutagenesis, and screening techniques. Even at this high level of skill, however, the effect of combining different heavy and light CDR substitutions on antigen binding could not have been readily predicted without additional testing. In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement (MPEP 2164.06). Thus, the level of skill does not obviate the need for substantial experimentation across the full scope of the claimed genus. Indeed, the inventor’s own disclosure demonstrates that identifying functional antibodies required extensive screening. In the absence of further guidance, artisans would necessarily have to engage in undue trial-and-error experimentation to generate and test numerous CDR combinations encompassed by the claim scope to determine which retain binding to human transferrin receptor. Claims 4-13 incorporate limitations of claim 1 but do not cure the deficiencies of claim 1 and thus are also rejected.
Therefore, the specification is not enabling over the full scope of the claims.
Double Patenting
Statutory Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1-15 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-15 of copending Application No. 19683976 (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented. The scope and language of the co-pending claims are identical to that of the instant claims having the same numbering. Thus, the co-pending claims anticipate the instant claims.
Non-Statutory 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.
Claim 1-5, 7-13, and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-65 of copending Application No. 19240131 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims recite a PRNP RNAi agent comprising double stranded RNA (dsRNA) linked to a protein comprising one monovalent human TfR binding domain, having a VH chain of SEQ ID NO: 7 and a VL chain of SEQ ID NO: 8 (co-pending claims 1 and 4). The amino acid sequences of the VH and VL chains are identical to SEQ ID NOs: 32 and 33, respectively, of the instant claims (see Sequence Alignments below). The VH chain of SEQ ID NO: 7 thus fully comprises the CDRs of SEQ ID NOs: 1, 10, and 11 of the instant claims; and the VL chain of SEQ ID NO: 8 thus fully comprises the CDRs of SEQ ID NOs: 9, 5, and 12 of the instant claims. In other embodiments, the human TfR binding domain comprises two heavy chains HC1 and HC2 and one light chain LC1, wherein HC1 comprises SEQ ID NO: 14, LC1 comprises SEQ ID NO: 10, and HC2 comprises SEQ ID NO:15 (co-pending claim 16). The X at position 379 of SEQ ID NO: 14 can be either alanine or cysteine; and the X at position 160 of SEQ ID NO: 15 can be either alanine or cysteine (see Sequence Listing of co-pending application). As such, the heavy chain HC1 of SEQ ID NO: 14— wherein X at position 379 is cysteine— is identical to SEQ ID NO: 68 of the instant claims; and the heavy chain HC2 of SEQ ID NO: 15—wherein X at position 160 is cysteine— is identical to SEQ ID NO: 69 of the instant claims. The light chain LC1 of SEQ ID NO: 10 is identical to SEQ ID NO: 59 of the instant claims (see Sequence Alignments below). Of note, the anti-TfR antibody recited in instant claim 1(a) reads on the elected anti-TfR species (clone TBD4), wherein X in SEQ ID NO: 21 is S, X1 in SEQ ID NO: 22 is R, and X2 in SEQ ID NO: 22 is N (see both Table 1 and Sequence Listing of instant specification). Further recited are embodiments wherein the human TfR binding domain is a Fab, scFv, Fv, or scFab (co-pending claim 5). The human TfR binding domain can additionally comprise a heavy chain constant region comprising cysteine at residue 124 according to the EU Index numbering (co-pending claim 6). The human TfR binding domain can also comprise a half-life extender selected form an Ig Fc region or a VHH that binds human serum albumin (HSA) (co-pending claims 7-9). In some embodiments, the Ig Fc region is a modified human IgG4 Fc region comprising proline at residue 228 and alanine at residues 234 and 245 according to EU index numbering (co-pending claims 10-11). In other embodiments, the Ig Fc region comprises cysteine at residue 378 according to EU numbering (co-pending claim 12). In still other embodiments, the IgG Fc region comprises (a) a first Fc CH3 domain comprising a serine at position 349, a methionine at position 366, a tyrosine at position 370, and a valine at position 409, and a second Fc CH3 domain comprising a glycine at position 356, an aspartic acid at position 357, a glutamine at position 346, and an alanine at position 407 according to EU numbering or (b) a first Fc CH3 domain comprising leucine at residue 405, and a second Fc CH3 domain comprising arginine at residue 409 according to EU numbering (co-pending claim 13).
VH chain: SEQ ID NO: 32 (instant claims) vs SEQ ID NO: 7 (co-pending claims).
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VL chain: SEQ ID NO: 33 (instant claims) vs SEQ ID NO: 8 (co-pending claims).
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Heavy chain CDRs of SEQ ID NOs 1, 10, and 12 (instant claims) fully comprised in VH chain of SEQ ID NO: 7 (co-pending claims).
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[AltContent: textbox (Light chain CDRs of SEQ ID NOs 9, 5, and 12 (instant claims) fully comprised in VH chain of SEQ ID NO: 8 (co-pending claims).)]
Light chain (or LC1) : SEQ ID NO: 59 (instant claims) vs SEQ ID NO: 10 (co-pending claims).
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HC1: SEQ ID NO: 68 (instant claims) vs SEQ ID NO: 14 (co-pending claims), wherein X at position 379 in SEQ ID NO: 14 is either Ala or Cys. When X is Cys, SEQ ID NO: 14 is 100% identical to SEQ ID NO: 68.
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HC2: SEQ ID NO: 69 (instant claims) vs SEQ ID NO: 15 (co-pending claims), wherein X at position 160 in SEQ ID NO: 15 is either Ala or Cys. When X is Cys, SEQ ID NO: 15 is 100% identical to SEQ ID NO: 69.
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Thus, the co-pending claims meet the limitations of the instant claims.
Claim 1-5, 7-13, and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-60 of copending Application No. 19042154 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims recite a SARM1 RNAi agent comprising double stranded RNA (dsRNA) linked to a protein comprising one monovalent human TfR binding domain, having a VH chain of SEQ ID NO: 7 and a VL chain of SEQ ID NO: 8 (co-pending claims 1 and 4). The amino acid sequences of the VH and VL chains are identical to SEQ ID NOs: 32 and 33, respectively, of the instant claims. The VH chain of SEQ ID NO: 7 thus fully comprises the CDRs of SEQ ID NOs: 1, 10, and 11 of the instant claims; and the VL chain of SEQ ID NO: 8 thus fully comprises the CDRs of SEQ ID NOs: 9, 5, and 12 of the instant claims. In other embodiments, the human TfR binding domain comprises two heavy chains HC1 and HC2 and one light chain LC1, wherein HC1 comprises SEQ ID NO: 14, LC1 comprises SEQ ID NO: 10, and HC2 comprises SEQ ID NO:15 (co-pending claim 15). The X at position 379 of SEQ ID NO: 14 can be either alanine or cysteine; and the X at position 160 of SEQ ID NO: 15 can be either alanine or cysteine (see Sequence Listing of co-pending application). As such, the heavy chain HC1 of SEQ ID NO: 14— wherein X at position 379 is cysteine— is identical to SEQ ID NO: 68 of the instant claims; and the heavy chain HC2 of SEQ ID NO: 15—wherein X at position 160 is cysteine— is identical to SEQ ID NO: 69 of the instant claims. The light chain LC1 of SEQ ID NO: 10 is identical to SEQ ID NO: 59 of the instant claims. Of note, the anti-TfR antibody recited in instant claim 1(a) reads on the elected anti-TfR species (clone TBD4), wherein X in SEQ ID NO: 21 is S, X1 in SEQ ID NO: 22 is R, and X2 in SEQ ID NO: 22 is N (see both Table 1 and Sequence Listing of instant specification). Further recited are embodiments wherein the human TfR binding domain is a Fab, scFv, Fv, or scFab (co-pending claim 5). The human TfR binding domain can additionally comprise a heavy chain constant region comprising cysteine at residue 124 according to the EU Index numbering (co-pending claim 6). The human TfR binding domain can also comprise a half-life extender selected form an Ig Fc region or a VHH that binds human serum albumin (HSA) (co-pending claims 7-9). In some embodiments, the Ig Fc region is a modified human IgG4 Fc region comprising proline at residue 228 and alanine at residues 234 and 245 according to EU index numbering (co-pending claims 10-11). In other embodiments, the Ig Fc region comprises cysteine at residue 378 according to EU numbering (co-pending claim 12). In still other embodiments, the IgG Fc region comprises (a) a first Fc CH3 domain comprising a serine at position 349, a methionine at position 366, a tyrosine at position 370, and a valine at position 409, and a second Fc CH3 domain comprising a glycine at position 356, an aspartic acid at position 357, a glutamine at position 346, and an alanine at position 407 according to EU numbering or (b) a first Fc CH3 domain comprising leucine at residue 405, and a second Fc CH3 domain comprising arginine at residue 409 according to EU numbering (co-pending claim 13).
VH chain: SEQ ID NO: 32 (instant claims) vs SEQ ID NO: 7 (co-pending claims).
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VL chain: SEQ ID NO: 33 (instant claims) vs SEQ ID NO: 8 (co-pending claims).
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Heavy chain CDRs of SEQ ID NOs 1, 10, and 12 (instant claims) fully comprised in VH chain of SEQ ID NO: 7 (co-pending claims).
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[AltContent: textbox (Light chain CDRs of SEQ ID NOs 9, 5, and 12 (instant claims) fully comprised in VH chain of SEQ ID NO: 8 (co-pending claims).)]
Light chain (or LC1) : SEQ ID NO: 59 (instant claims) vs SEQ ID NO: 10 (co-pending claims).
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HC1: SEQ ID NO: 68 (instant claims) vs SEQ ID NO: 14 (co-pending claims), wherein X at position 379 in SEQ ID NO: 14 is either Ala or Cys. When X is Cys, SEQ ID NO: 14 is 100% identical to SEQ ID NO: 68.
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HC2: SEQ ID NO: 69 (instant claims) vs SEQ ID NO: 15 (co-pending claims), wherein X at position 160 in SEQ ID NO: 15 is either Ala or Cys. When X is Cys, SEQ ID NO: 15 is 100% identical to SEQ ID NO: 69.
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Thus, the co-pending claims meet the limitations of the instant claims.
Claim 1-13 and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-62 of copending Application No. 18806842 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims recite a APP RNAi agent comprising double stranded RNA (dsRNA) linked to a protein comprising one monovalent human TfR binding domain, having a VH chain of SEQ ID NO: 7 and a VL chain of SEQ ID NO: 8 (co-pending claims 1 and 4). The amino acid sequences of the VH and VL chains are identical to SEQ ID NOs: 32 and 33, respectively, of the instant claims. The VH chain of SEQ ID NO: 7 thus fully comprises the CDRs of SEQ ID NOs: 1, 10, and 11 of the instant claims; and the VL chain of SEQ ID NO: 8 thus fully comprises the CDRs of SEQ ID NOs: 9, 5, and 12 of the instant claims. In other embodiments, the human TfR binding domain comprises two heavy chains HC1 and HC2 and one light chain LC1, wherein HC1 comprises SEQ ID NO: 14, LC1 comprises SEQ ID NO: 10, and HC2 comprises SEQ ID NO:15 (co-pending claim 16). The X at position 379 of SEQ ID NO: 14 can be either alanine or cysteine; and the X at position 160 of SEQ ID NO: 15 can be either alanine or cysteine (see Sequence Listing of co-pending application). As such, the heavy chain HC1 of SEQ ID NO: 14— wherein X at position 379 is cysteine— is identical to SEQ ID NO: 68 of the instant claims; and the heavy chain HC2 of SEQ ID NO: 15—wherein X at position 160 is cysteine— is identical to SEQ ID NO: 69 of the instant claims. The light chain LC1 of SEQ ID NO: 10 is identical to SEQ ID NO: 59 of the instant claims. Of note, the anti-TfR antibody recited in instant claim 1(a) reads on the elected anti-TfR species (clone TBD4), wherein X in SEQ ID NO: 21 is S, X1 in SEQ ID NO: 22 is R, and X2 in SEQ ID NO: 22 is N (see both Table 1 and Sequence Listing of instant specification). Further recited are embodiments wherein the human TfR binding domain is a Fab, scFv, Fv, or scFab (co-pending claim 5). The human TfR binding domain can additionally comprise a heavy chain constant region comprising cysteine at residue 124 according to the EU Index numbering (co-pending claim 6) or a light chain constant region comprising cysteine at residue 156 according to EU index numbering (co-pending claim 7). The human TfR binding domain can also comprise a half-life extender selected form an Ig Fc region or a VHH that binds human serum albumin (HSA) (co-pending claims 8-10). In some embodiments, the Ig Fc region is a modified human IgG4 Fc region comprising proline at residue 228 and alanine at residues 234 and 245 according to EU index numbering (co-pending claims 11-12). In other embodiments, the Ig Fc region comprises cysteine at residue 378 according to EU numbering (co-pending claim 13). In still other embodiments, the IgG Fc region comprises (a) a first Fc CH3 domain comprising a serine at position 349, a methionine at position 366, a tyrosine at position 370, and a valine at position 409, and a second Fc CH3 domain comprising a glycine at position 356, an aspartic acid at position 357, a glutamine at position 346, and an alanine at position 407 according to EU numbering or (b) a first Fc CH3 domain comprising leucine at residue 405, and a second Fc CH3 domain comprising arginine at residue 409 according to EU numbering (co-pending claim 14).
VH chain: SEQ ID NO: 32 (instant claims) vs SEQ ID NO: 7 (co-pending claims).
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VL chain: SEQ ID NO: 33 (instant claims) vs SEQ ID NO: 8 (co-pending claims).
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Heavy chain CDRs of SEQ ID NOs 1, 10, and 12 (instant claims) fully comprised in VH chain of SEQ ID NO: 7 (co-pending claims).
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[AltContent: textbox (Light chain CDRs of SEQ ID NOs 9, 5, and 12 (instant claims) fully comprised in VH chain of SEQ ID NO: 8 (co-pending claims).)]
Light chain (or LC1) : SEQ ID NO: 59 (instant claims) vs SEQ ID NO: 10 (co-pending claims).
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HC1: SEQ ID NO: 68 (instant claims) vs SEQ ID NO: 14 (co-pending claims), wherein X at position 379 in SEQ ID NO: 14 is either Ala or Cys. When X is Cys, SEQ ID NO: 14 is 100% identical to SEQ ID NO: 68.
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772
650
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HC2: SEQ ID NO: 69 (instant claims) vs SEQ ID NO: 15 (co-pending claims), wherein X at position 160 in SEQ ID NO: 15 is either Ala or Cys. When X is Cys, SEQ ID NO: 15 is 100% identical to SEQ ID NO: 69.
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436
674
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Thus, the co-pending claims meet the limitations of the instant claims.
Claims 1, 2, 4, 7, and 8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-62 of copending Application No. 18746732 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims recite a compound comprising a progranulin domain and a TfR binding domain wherein the TfR1 binding domain comprises a VH and VL chains, wherein the VH chain has the CDRs of SEQ ID NOs: 45, 46, and 47 and the VL chain has the CDRs of SEQ ID NOs: 48, 49, and 50. The heavy chain CDRs are identical to SEQ ID NOs: 1, 10, and 11 of the instant claims; and the light chain CDRs are identical to SEQ ID NOs: 9, 5, and 12 of the instant claims (see Sequence Alignments below). The Tfr1 binding domain can be a Fab fragment (co-pending claims 7-8). The compound can further comprise an albumin binding domain (half-life extender) that is VHH (co-pending claims 2, 15, and 16). Of note, the anti-TfR antibody recited in instant claim 1(a) reads on the elected anti-TfR species (clone TBD4), wherein X in SEQ ID NO: 21 is S, X1 in SEQ ID NO: 22 is R, and X2 in SEQ ID NO: 22 is N (see both Table 1 and Sequence Listing of instant specification).
HCDR1: SEQ ID NO: 1 (instant claims) vs SEQ ID NO: 45.
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274
762
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HCDR2: SEQ ID NO: 10 (instant claims) vs SEQ ID NO: 46.
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266
768
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HCDR3: SEQ ID NO: 11 (instant claims) vs SEQ ID NO: 47.
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264
770
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LCDR1: SEQ ID NO: 9 (instant claims) vs SEQ ID NO: 48.
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292
764
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LCDR2: SEQ ID NO: 5 (instant claims) vs SEQ ID NO: 49.
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258
768
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LCDR3: SEQ ID NO: 12 (instant claims) vs SEQ ID NO: 50.
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260
768
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Thus, the co-pending claims meet the limitations of the instant claims.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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