DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1 and 44-62, of record 8/24/25, are pending and subject to prosecution.
Election/Restrictions
Applicant’s species election of VH and VL sequences targeting CD19 antigen for claims 49, 50, 60 and 61, encoded by claimed vH SEQ ID NOs 14431, 16223, 16264, and 16295, and vL SEQ ID NOs: 14400, 16140, 16171 and 16202, in the reply filed on 8/24/25 is acknowledged. 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 1 and 44-62 read on the elected species.
The Restriction Requirement of 6/24/25 was sent in response to Applicant’s amendments to the claims of 3/05/25, wherein claims 2-4, 8, 10-12, 14, 16-18, 21, 23, 27, 29-36 and 38-39 were cancelled, and claims 44-62 were newly added. Applicant’s claims of 03/05/25 were in response to a non-final office action mailed 09/05/2024.
STATUS OF REJECTIONS
The 9/05/2024 objection to claims 1-4, 7, 11, 14, 16-17, 27, 29, 31-33 and 39 is withdrawn. Applicant’s cancellation of claims 2--4, 7, 11, 14, 16-17, 27, 29, 31-33 and 39, as well as Applicant’s amendments to claim 1 are sufficient to overcome all objections of record.
The 9/05/2024 112b rejection of claims 1-4, 8, 10-12, 14, 16-18, 21, 23, 27, 29-36 and 39 is withdrawn. Applicant’s cancellation of claims 2-4, 8, 10-12, 14, 16-18, 21, 23, 27, 29-36 and 39, as well as Applicant’s amendments to claim 1 are sufficient to overcome all 112b rejections of record.
The 9/05/2024 103 rejection of claims 1-4, 8, 10-12, 14, 16, 18, 21, 23, 27, 29-36 and 38-39, as obvious over Yang in view of Brogdon is withdrawn. Applicant’s cancellation of claims 2-4, 8, 10-12, 14, 16, 18, 21, 23, 27, 29-36 and 39, as well as Applicant’s amendments to claim 1 are sufficient to overcome the rejection.
The 9/05/2024 103 rejection of claim 17 as obvious over Yang and Brogdon, further in view of Lu is withdrawn. Applicant’s cancellation of claim 17 is sufficient to overcome the rejection.
RESPONSE TO ARGUMENTS
Applicant’s arguments filed 3/05/25 with regard to the prior art rejections have been considered but are not fully persuasive. Applicant argues that the amendment to claim 1, directed to a chimeric synthetic immune receptor (zSIR) construct encoding a 2-chain receptor, wherein the vL and vH domains attached to two separate CD3z chains, is not taught or suggested by the prior art (Yang, Brogdon, Lu) (pages 15-23, 25-27, 30). The examiner agrees that none of the cited art discloses a two-chain chimeric immune receptor, wherein a first chain encodes a vH segment from an antibody operably linked to a CD3z chain comprising a CD3z transmembrane domain, and a second chain encodes a vL segment from the antibody operably linked to a CD3z chain comprising a CD3z transmembrane domain as newly claimed. Rather the prior art of record disclose wherein the vH and vL of an antibody are encoded in a single-chain format (Yang, Brogdon) or a two-chain TCR, wherein a first chain encodes a VH segment from an antibody operably linked to a TCR chain transmembrane domain, and a second chain encodes a VH segment from an antibody operably linked to a TCR chain transmembrane domain (Lu) when utilized in generating TCR or CARs in recombinant immune cells. It is for this reason the prior art rejections of record have been withdrawn.
At pages 19 and 29 of the Reply, Applicant argues that the prior art teaches away from the use of chimeric TCR receptors, or a two-chain chimeric immune receptor format. Applicant points to the Gross & Eshhar, of 1992, who disclose using cTCR (a two-chain immune receptor) is technically difficult because it requires co-expressing both chains in a cell, and that the single-chain format was preferred to simplify construction and delivery (Eshhar, Waks, & Gross, 2014).
The Examiner is not persuaded. The use of two-chain chimeric immune receptors is, and remains, a viable option for generating antigen-specific T-cells at the time of filing– as demonstrated by Yang (of record), Lu (of record), Grovers, 2011 (of record, cited on Applicant’s IDS dated 9/09/2022), and Applicant’s cited Eshhar, Waks, & Gross, 2014.
Yang discloses methods of generating recombinant antigen-specific T-cells expressing two-chain recombinant TCRs. Yang discloses its methods of encoding both chains of the receptor on the same construct, wherein the constructs are codon-optimized, overcomes the technical challenges of expressing the proteins in a cell (Abstract, paragraphs [0001]-[0007]).
Lu’s disclosure, published 4/27/207, is related to expressing recombinant 2 chain TCR comprising antibody binding domains in T cells, wherein the TCR comprises a first chain encodes a vH segment from an antibody operably linked to a TCR chain transmembrane domain and a heterologous intracellular signaling domain, and a second chain encodes a vH segment from an antibody operably linked to a TCR chain transmembrane domain, and an intracellular signaling domain (abstract; paragraphs [0080]-[0084]), FIGs 28-32).
Grovers, 2011 (of record) discloses gene therapy comprising recombinant TCR transgenes “represents a feasible and promising treatment for patients with cancer and virus infections” (Abstract). Grovers discloses problems associated with recombinant TCR expression mispairing in T-cells can be overcome by use of a CD3z transmembrane domain (abstract, FIGs 1-3, 5).
Eshhar, Waks, & Gross, 2014 disclose T-cells expressing recombinant TCRs specific for Epstein-virus and a CAR specific for CD2 have been successfully used in patients (page 125).
Applicant additionally argues the pending claims are distinct from the prior art because they bind to antigens in an HLA independent manner (page 20-21). It is noted that the claims do not require wherein the receptor binds in an HLA independent manner.
Applicant additionally argues that the pending claims are not taught by the prior art because the claims require peptide linkers between the antigen variable domains and the CD3z constant domains. Applicant argues “linkers between the vL and vH fragments and the CD3z chains do not simply function to fuse the two polypeptides but confer unexpected functional biological properties on the zSIR, including increased expression and activity” (pages 23-24). The Examiner is not persuaded. Initially, the Examiner notes the independent claims do not require linkers. Rather, linkers are optional in each of claims 1, 56, and 62. In addition, while the Examiner agrees that the specification states that the presence of linkers confers biological properties such as increased expression and activity, the Examiner is unable to find any evidence supporting this statement. There do not appear to be any functional studies comparing the function of the same zSIR with and without the same linker, which would support Applicant’s assertion. In addition, the specification broadly defines “linker,” and appears to contradict Applicant’s assertion that linkers “do not simply function to fuse two polypeptides.” Paragraph [0108] of the published specification teaches, “As used herein, the term ‘linker’ (also ‘linker domain’ or ‘linker region’) refers to an oligo or polypeptide that joins together two or more domains or regions of a CAR (e.g., 2nd generation CAR, TFP, AbTCR, SIR and zSIR) disclosed herein. The linker can be anywhere from 1 to 500 amino acids in length.”
Applicant additionally argues the pending claims have technical advantages over the prior art. Applicant argues the claimed receptors can be expressed in cells other than T-cells, such as NK cells, because the chimeric receptors of Brogdon and Lu require the presence of endogenous CD3z (pages 31-32). This is not persuasive. Initially, the pending claims do not require wherein the receptor is expressed in any particular cell. In addition, Yang discloses two-chain chimeric TCR receptors can be operably linked to a heterologous CD3z intracellular domain and expressed in cells other than T-cells, including NK cells and stem cells (paragraph [0024]). Thus, such constructs would not require the use of endogenous CD3z signaling.
Applicant argues that receptors encompassed by the present claims have shown high expression, cytotoxic activity, and NF-κB activation in CD19+ cells compared to a 2nd generation CAR construct (pages 32-34). The data presented is taken from WO20222178367, wherein SEQ ID NO: 5141 is the single-chain CD19 CAR, whereas the other listed sequences represent receptors of the present invention.
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Applicant produces Table 51 of WO ’367 demonstrating the chimeric receptor’s ability to bind CD19 (SEQ ID NOs: 2275, 2278, 2277 = recombinant receptors according the invention; SEQ ID NO: 5141 = CD19-CAR):
Applicant produces Table 52 of WO ’367 demonstrating the chimeric receptor’s cytotoxicity when cells expressing the receptors are cultured in the presence of target cell lines (SEQ ID NOs: 2275, 2278, 2277 = recombinant receptors according the invention; SEQ ID NO: 5141 = CD19-CAR):
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Applicant produces Table 53 of WO ’367 demonstrating the chimeric receptor’s ability to activate NF-κB in cells expressing the receptors, when the cells are cultured in the presence of CD19 target cell lines (SEQ ID NOs: 2275, 2277, 1860 = recombinant receptors according the invention; SEQ ID NO: 5141 = CD19-CAR):
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Applicant’s evidence of unexpected results is not persuasive. The burden is on Applicant to establish the results are unexpected with regard to the claimed invention MPEP716.02(b): “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance;” and the evidence provided must be commensurate with the scope of the claimed invention (MPEP 716.02(d)).
Applicant does not articulate how the three zSIR receptors of WO’367 are encompassed by the structures of the instant claims, or how the zSIR receptors of WO’367 are structurally similar to, or different from the tested CD19-CAR, or the chimeric immune receptors of the cited prior art. Applicant does not articulate what structural difference results in any specific difference in efficacy allegedly shown in the tables presented. Are the antigen-binding domains the same? Are the same intracellular signaling domains used?
In addition, the data presented is of three zSIR in comparison to a single CAR, and of that data, the three zSIR do not outperform the CD19-CAR in every test. The Examiner notes that the CD19-CAR of Table 51 shows increased CD19 binding compared to the receptors 2278 and 2275. The CD19-CAR does not appear to be statistically different that receptor 2278 in Table 52. The CD19-CAR has higher NF-kb activation in CD19 Raji cells compared to all three receptors tested, on average, and lower NF-kb activation that 2/3 receptors tested in CD19-KO cells, on average.
Thus, it is unclear how these results demonstrate unexpected results, or, how such results represent the claimed receptors and any specific structure therein. Rather, it would appear that applicant has shown that two-chain chimeric receptors function in an expressed cell, as expected.
Applicant additionally argues that the zSIR receptors encompassed by the present claims can generate multi-specific constructs, which may aid in overcoming the loss of potency that may occur in following expression in T-cells (Pages 34-35 of the Reply). The examiner is not persuaded. The instant claims do not require a bispecific or multi-specific receptor.
PRIORITY
The instant application, filed 12/01/2020 is a 371 National Stage Application of PCT/US2019/035096, filed 06/01/2019, which claims priority to US Provisional Application No. 62/679,741, filed 06/01/2018. Thus, the earliest possible priority for the instant application is 06/01/2018.
CLAIMS
Independent claim 1 has been amended with the claims of 3/5/25, and independent claims 56 and 62 are newly added as of 3/5/25. The claims are generally directed to Synthetic Chimeric Immune Receptors (zSIRs) and nucleic acids encoding them, wherein the zSIRs are two-chain heterodimer receptors comprising two CD3z chains (or fragments thereof) having CD3z transmembrane domains (or a functional portion of), and a variable heavy chain (vH) and a variable light chain (vL) domain fragment of the same antibody, comprising optional linkers.
Claim 1 requires wherein the vH and vL fragments each are “joined” to one of the CD3z chains.
Claims 56 and 62 require wherein
a) the vH and vL fragments each are operably linked “directly” to one of the CD3z chains; or
b) the vH and vL fragments each are operably linked to one of the CD3z chains with a linker.
CLAIM INTERPRETATION
The specification defines CD3z chains “as the protein provided as GenBank Accession No. BAG36664.1, or the equivalent residues from a non-human species…is defined as the amino acid residues from the cytoplasmic domain of the zeta chain, or functional derivatives thereof, that are sufficient to functionally transmit an initial signal necessary for T cell activation.” Paragraph [0128]. Thus, a “CD3z chain” includes the entire cytoplasmic domain, or functional derivatives thereof.
The structure explicitly required in the claimed zSIRs is minimal:
a) a heterodimer of two cytoplasmic domains of CD3z, each with a CD3z transmembrane domain;
b) a vH fragment and a vL fragment from the same antibody; wherein
i) the vH and vL fragments each are “joined” to one of the CD3z chains (claim 1), which allows for intervening peptide sequences between the vH and vL fragments and the CD3z chain; and
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ii) the vH and vL fragments each are operably linked “directly” to one of the CD3z chains, which does not allow for any non-CD3z peptide or non-antibody fragments between the vH domain and vL domains and the CD3z chain:
However, as noted above the claims also encompass “fragments” of the two CD3z chains having “functional portions” of a CD3z transmembrane domain. The specification defines fragments and functional portions of the receptors at paragraph [0095]:
“The term ‘functional portion’ when used in reference to, e.g., a zSIR refers to any part or fragment of a polypeptide, e.g., the zSIR, which part or fragment retains the biological activity of the desired molecule, e.g., of the zSIR, of which it is a part (e.g., the parent zSIR). For example, functional portions encompass those parts of a zSIR that retain the ability to recognize target cells, or detect, treat, or prevent a disease, to a similar extent, the same extent, or to a higher extent, as the parent zSIR. In reference to the parent zSIR, the functional portion can comprise, for instance, about 10%, 25%, 30%, 50%, 68%, 80%, 90%, 95%, or more, of the parent zSIR.”
Thus, the specification discloses “fragments” and “functional portions” of a specific domain allow for
1) smaller peptide segments of a domain, wherein the smaller segments have 100% identity to the corresponding segment of the parent sequence, and retain the function of the parent peptide domain; and
2) peptides with as little as 10% homology to the parent peptide domain, so long as the peptides retain the function of the parent peptide domain.
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The function of the claimed zSIRs and/or their domains is defined in the specification:
vH and vL fragments are defined as “at least one portion of an antibody, that retains the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing/destabilizing, spatial distribution) an epitope of an antigen.” Paragraph [0040].
CD3z chains are “the amino acid residues from the cytoplasmic domain of the zeta chain, or functional derivatives thereof, that are sufficient to functionally transmit an initial signal necessary for T cell activation.” Paragraph [0128].
Thus, the zSIRs (nucleic acids or peptides encoded by) of the independent claims encompass, at least:
a first protein chain comprising a vH domain fragment from an antibody operably linked to a CD3z intracellular domain comprising a CD3z transmembrane domain; and
a second protein chain comprising a vL domain fragment from the antibody operably linked to a CD3z intracellular domain comprising a CD3z transmembrane domain,
wherein expression of the first protein chain and the second protein chain form heterodimers, and wherein the vH domain fragment and/or vL domain fragment are able to bind the target antigen of the parent antibody.
The instant claims do not require any specific mechanism that results in the heterodimerism of the two peptide chains.
In addition, the language used to claim specific SEQ ID NOs. recited in claims 44, 45, 48, 49, 59, and 61 is affecting whether the claimed sequences are limited to the full-length sequence, or if the scope is broader and includes fragments of the claimed sequences.
Claim 44 requires wherein the CD3z chains comprise one or more co-stimulatory domains, wherein “the encoded co-stimulatory domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 4067, 4068.” The broadest reasonable interpretation of the scope encompassed by the claim claimed phrase includes the full-length sequence of 4067 or 4068, or any dimer encoded within the claimed sequences. Amendment to “the amino acid sequence selected from the group consisting of” would limit the scope to the full-length sequences.
Claim 45 requires “a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 4064; 4066; 4075; and 4076.” The broadest reasonable interpretation of the scope encompassed by the claimed phrase includes the full-length sequence of 4064, 4066, 4075 or 4076, or any dimer encoded within the claimed sequences. Amendment to “the sequence selected from the group consisting of” would limit the scope to the full-length sequences.
Claim 48 requires “a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 4028-4035.” The broadest reasonable interpretation of the scope encompassed by the claimed phrase includes the full-length sequence of 4028-4035, or any dimer encoded within the claimed sequences. Amendment to “the sequence selected from the group consisting of” would limit the scope to the full-length sequences.
Claim 49 requires,
”a complementarity determining region 1 (CDR1) amino acid sequence of SEQ ID NOs.:11961-12066 and 16126-16155” in lines 2-3;
“a CDR2 amino acid sequence of SEQ ID NOs: 12062-12173 and 16157-16186” in lines 3-4;
“a CDR3 amino acid sequence of SEQ ID NOs: 12175-12280 and 16188-16217” in lines 4-5;
“a complementarity determining region 1 (CDR1) amino acid sequence of SEQ ID NOs: 12282-12387 and 16219-16248” in lines 12-13; and
“a CDR2 amino acid sequence of SEQ ID NOs: 12389-12494 and 16250-16279” in lines 13-14.
The broadest reasonable interpretation of the scope encompassed by the claimed phrases includes the full-length sequence of each sequence listed, or any dimer encoded within the claimed sequences. Amendment to “the CDR…” would limit the scope to the full-length sequences.
Claim 59 requires “a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 4064, 4066, 4075, and 4076.” The broadest reasonable interpretation of the scope encompassed by the claimed phrase includes the full-length sequence of 4064, 4066, 4075 or 4076, or any dimer encoded within the claimed sequences. Amendment to “the sequence selected from the group consisting of” would limit the scope to the full-length sequences.
Claim 61 requires:
“a sequence selected from SEQ ID NOs 4192-4264,9662-9691, 11464-11466, 14417-14446;” and
“a sequence selected from SEQ ID Nos. 4118-4190, 9631-9660, 11460-11462, 14386-14415.”
The broadest reasonable interpretation of the scope encompassed by the claimed phrases includes the full-length sequence of each sequence listed, or any dimer encoded within the claimed sequences. Amendment to “the sequence selected from” would limit the scope to the full-length sequences.
Claim Objections
Claims 1, 45, 46, 47, 50, 53 and 60-61 are objected to because of the following informalities:
Claim 1 recites “fragment” instead of “fragments” in line 7.
Claim 45 recites “the group consisting of SEQ ID NOs: 4064; 4066; 4075; and 4076.” Applicant should amend the claim and replace the semicolons with commas.
Claim 47 is missing the word “and” at the end of line (iv), between the Markush groups listed.
Claim 50 repeats antigens VEGFR2, B7-H3, fucosyl-GM1, HMW-MAA (with the equivalent CSPG4-HMW-MAA), GPRC5D, NY-BR1, HAVCR1 (repeated as equivalent “TIM-1 (HAVCR1)”), IL-11Rα repeated as IL11Rα, IL-13Rα2 repeated as IL13Rα2, and CLDN6.
The same objection is made over claim 60. Applicant is requested to review claims 50 and 60 for any additional repeated antigens.
Claims 53 has a semicolon after “claim 1;” instead of a comma.
Claim 61 is missing the word “of” at line 3, and should recite, “a vH fragment of an antibody.”
Claim 61 recites “SEQ ID NOs” in line 3, which is missing a colon. The claim further recites “SEQ ID Nos.” in lines 7-8 which should be amended to capitalize the “NOs” and replace the period with a colon, in order to make the formatting consistent with the rest of the claim set.
Claim 61 requires inserting the word “and” into the Markush group “SEQ ID NOs 4192-4264,9662-9691, 11464-11466, and 14417-14446” of lines 3-4, and “SEQ ID Nos. 4118-4190, 9631-9660, 11460-11462, and 14386-14415” in lines 7-8.
Appropriate correction is required.
Claim Rejections - 35 USC § 112- indefinite
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 44, 46, 49-50 and 60 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 44 is rejected for the use of parentheticals. Claim 44 recites “CD134 (OX40)” in line 5. It is not clear whether the parenthetical is used to indicate a limitation, a preferred embodiment (a suggestion of one species of the adjacent protein), or synonym, etc. An acronym can be spelled out at the first encounter in a claim, but in the instant claim, the parentheticals do not merely spell out an acronym. Accordingly, the metes and bounds of the claim are not clear. If the parenthetical matter is a limitation to remain in the claim, then the parentheses must be replaced with commas. Alternatively, deletion of the term within the parentheticals would obviate this rejection.
Claim 46, dependent upon claim 1 (encompassing a polynucleotide composition) recites, “The at least one recombinant polynucleotide of claim 1 co-expressed with a nucleic acid encoding an accessory module” which is indefinite (emphasis added). Initially, it is not clear is the claim is attempting to require whether the polynucleotide of claim 1 further encode the nucleic acids encode the accessory module, or if the claimed nucleic acids encoding an accessory module are separate (is not-colinear or operably linked). If the latter, then the claim is indefinite for claiming both a composition and method of using a composition.
A single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112(b). See In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303, 1318, 97 USPQ2d 1737, 1748-49 (Fed. Cir. 2011). In Katz, a claim directed to "[a] system with an interface means for providing automated voice messages…to certain of said individual callers, wherein said certain of said individual callers digitally enter data" was determined to be indefinite because the italicized claim limitation is not directed to the system, but rather to actions of the individual callers, which creates confusion as to when direct infringement occurs. Katz, 639 F.3d at 1318, 97 USPQ2d at 1749 (citing IPXL Holdings v. Amazon.com, Inc., 430 F.3d 1377, 1384, 77 USPQ2d 1140, 1145 (Fed. Cir. 2005), in which a system claim that recited "an input means" and required a user to use the input means was found to be indefinite because it was unclear "whether infringement … occurs when one creates a system that allows the user [to use the input means], or whether infringement occurs when the user actually uses the input means."); Ex parte Lyell, 17 USPQ2d 1548 (Bd. Pat. App. & Inter. 1990).
In the instant case, the claim encompasses a polynucleotide encoding a zSIR and co-expressing the zSIR with additional nucleotides encoding accessory modules.
Claim 49 recites the limitation "the vL domain" in line 6. There is insufficient antecedent basis for this limitation in the claim.
Claim 49 recites the limitation "the vH domain" in line 16. There is insufficient antecedent basis for this limitation in the claim.
Claim 49 encompasses protein and nucleotide sequences by SEQ ID NO which encode the CDR1-CDR3 of the vH fragment and vL fragment encoded in the zSIR of claim 1. Claim 1 requires that the vH and vL fragments come from the same antibody. The claim requires, at least, wherein
a) the encoded vL fragment contains
a CDR1 amino acid sequence of SEQ ID NOs.:11961-12066 and 16126-16155,
a CDR2 amino acid sequence of SEQ ID NOs: 12062-12173 and 16157-16186, and
a CDR3 amino acid sequence of SEQ ID NOs: 12175-12280 and 16188-16217,
wherein the polynucleotide encoding the vL domain is at least 80% identical to the nucleotide sequence of SEQ ID Nos. 155-227, 8000-8029, 11300-11302, and 12642-12671,
provided that the vL domain comprises
the CDR1 amino acid sequence of SEQ ID NOs:11961-12066 and 16126-16155,
the CDR2 amino acid sequence of SEQ ID NOs: 12068-12173 and 16157-16186, and
the CDR3 amino acid sequence of SEQ ID NOs:12175-12280 and 16188-16217; and
b) the encoded vH fragment contains
a CDR1 amino acid sequence of SEQ ID NOs: 12282-12387 and 16219-16248,
a CDR2 amino acid sequence of SEQ ID NOs: 12389-12494 and 16250-16279, and
the CDR3 amino acid sequence of SEQ ID NOs: 12497-12602 and 16281-16310,
wherein the polynucleotide encoding the vH domain is at least 80% identical to the nucleotide sequence of SEQ ID NOs: 229-301, 8031-8060, 11304-11306, and 12673-12702,
provided that the vH domain comprises
the CDR1 amino acid sequence of SEQ ID NOs:12282-12387 and 16219-16248,
the CDR2 amino acid sequence of SEQ ID NOs: 12389-12494 and 16250-16279, and
the CDR3 amino acid sequence of SEQ ID NOs:12497-12602 and 16281-16310.
The skilled artisan would not know from the claim as written which three vL CDRs 1-3 are encoded on the same antibody, and which three vH CDRs 1-3 are encoded on the same antibody, and whether the three vL CDRs 1-3 selected are sourced from the same antibody as the three vH CDRs 1-3 selected. If the claim is written such that the respective order of the vL CDR1 sequences determines the order of the vL CDR2 sequences and the vL CDR3 sequences, and/or the vH CDR sequences, Applicant must amend the claim to make these relationships clear. In addition, the claim must be amended to make clear which nucleic acid sequence is encoding which CDRs.
Claim 50 is rejected for the use of parentheticals throughout the claim. Claim 50 recites use of parentheticals including, but not limited to:
“CS1 (CD2 subset 1, CRACC, SLAMF7, CD319, or 19A24)” in lines 4-5;
“C-type lectin-like molecule-1 (CLL-1 or CLECL1)” in line 5;
“B7-H3 (CD276)” in line 13;
“KIT (CD 117)” in line 13; and
“interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2)” in lines 13-14.
It is not clear whether the parentheticals are used to indicate a limitation, a preferred embodiment (a suggestion of one species of the adjacent protein), or synonym, etc. An acronym can be spelled out at the first encounter in a claim, but in the instant claim, the parentheticals do not merely spell out an acronym. Accordingly, the metes and bounds of the claim are not clear. If the parenthetical matter is a limitation to remain in the claim, then the parentheses must be replaced with commas. Alternatively, deletion of the terms within the parentheticals would obviate this rejection. Applicant should review the use of parentheticals throughout the claim and amend as necessary.
Claim 60 is rejected for the use of parentheticals throughout the claim, for the same reasons as stated above for claim 50.
Claim 61 embodies peptide sequences encoding the vH fragment and vL fragment of the zSIR heterodimer, wherein the fragments comprise:
a vH fragment of an antibody having a sequence selected from SEQ ID NOs 4192-4264,9662-9691, 11464-11466, 14417-14446,… and
a complementary vL fragment of the antibody having a sequence selected from SEQ ID Nos. 4118-4190, 9631-9660, 11460-11462, 14386-14415….
Initially, it is unclear whether the claimed sequences are modifying the vH fragment/vL fragment or the antibody from which the fragments come from? Does the claim encompass:
“a vH fragment comprising the sequence selected from the group consisting of SEQ ID NOs: 4192-4264…and a complementary vL fragment comprising the sequence selected from the group consisting of SEQ ID NOs 4118-4190” or
“a vH fragment of an antibody, wherein the antibody comprises the sequence selected from the group consisting of SEQ ID NOs: 4192-4264…and a complementary vL fragment of the antibody, wherein the antibody comprises the sequence selected from the group consisting of SEQ ID NOs 4118-4190”?
Claim 61 embodies peptide sequences encoding the vH fragment and vL fragment of the zSIR heterodimer, wherein the fragments comprise:
a vH fragment of an antibody having a sequence selected from SEQ ID NOs 4192-4264,9662-9691, 11464-11466, 14417-14446, or a sequence containing at least the three heavy chain CDRs corresponding to any of the foregoing sequences; and
a complementary vL fragment of the antibody having a sequence selected from SEQ ID Nos. 4118-4190, 9631-9660, 11460-11462, 14386-14415, or a sequence containing at least the three light chain CDRs corresponding to any of the foregoing sequences.
It is unclear whether the CDR sequences which “correspond” to the claimed SEQ ID NOs are the specific CDR amino acid residues recited in the SEQ ID NOs (with 100% identity); or whether the CDR sequences “correspond” by function, such that the sequences encoding the CDRs of the SEQ ID NOs may comprise substitutions, so long as the binding function of the CDRs comprising the corresponding amino acid residues retain the binding of the parent antibody sequence? The Examiner notes the term “corresponding” is used within the specification in both manners.
In addition, the recitation of Claim 61 of “a vH fragment an antibody having a sequence selected from SEQ ID NOs 4192-4264, 9662-9691, 11464-11466, 14417-14446; …. and a complementary vL fragment of the antibody having a sequence selected from SEQ ID Nos. 4118-4190, 9631-9660, 11460-11462, 14386-14415…” renders the claim indefinite.
The skilled artisan would not know from the claim as written that the complement vL sequence is presented in the same order as the vH fragments. As written, the claim is interpreted as a specific complementary vL fragment could be any among those listed, and thus are not sourced from the same antibody. Applicant must amend the claim to make clear that a complement vL fragment is in respective order of the vH fragment order. Accordingly, the metes and bounds of the claim are not clear.
Claim Rejections - 35 USC § 112 -scope of enablement
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.
Claim 55 is 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 methods of treating a disease associated with the expression of a disease-associated antigen, wherein the disease includes cancer, does not reasonably provide enablement for methods of preventing a disease associated with the expression of a disease-associated antigen, wherein the disease includes cancer. 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 and use the invention commensurate in scope with these claims.
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 and use the invention commensurate in scope with these claims. Claim 55 is drawn in part to a method of treating or preventing any disease or disorder listed, including cancer in a subject comprising administering to the subject an effective amount of recombinant cells comprising a zSIR, ultimately of claim 1. The prior art appears to be silent with regard to demonstrating prevention of any of the listed diseases using recombinant cells comprising a zSIR, TCR, or chimeric antigen receptor. Furthermore, the instant specification fails to exemplify such prevention. While it may be argued that the scope of the term "prevention" embraces delaying the onset or reducing the severity of any and all symptoms of any of the disorders and diseases listed, the invention as claimed nevertheless also embraces full and complete prevention of any and all symptoms of any of the disorders and diseases listed using the recited steps. The full scope of the claim term "prevention" is thus not enabled as it regards prevention of the recited disorder or disease listed, since at best it would require undue trial and error experimentation, the outcome of which is highly unpredictable. Amendment to remove this term would be remedial.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 and 44-62 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.
Claims 1, 56 and 62 are directed to zSIR heterodimers, or nucleic acids encoding them, comprising, at least,
a first chain comprising a vH fragment from an antibody, a CD3z transmembrane domain “or functional portion of” and a CD3z chain “or fragment thereof;” and
a second chain comprising a vL fragment from the antibody, a CD3z transmembrane domain “or functional portion of” and a CD3z chain “or fragment thereof.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
An applicant shows that the inventor was in possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the inventor was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991).
For some biomolecules, examples of identifying characteristics include a sequence, structure, binding affinity, binding specificity, molecular weight, and length. Although structural formulas provide a convenient method of demonstrating possession of specific molecules, other identifying characteristics or combinations of characteristics may demonstrate the requisite possession. As explained by the Federal Circuit, "(1) examples are not necessary to support the adequacy of a written description; (2) the written description standard may be met … even where actual reduction to practice of an invention is absent; and (3) there is no per se rule that an adequate written description of an invention that involves a biological macromolecule must contain a recitation of known structure." Falkner v. Inglis, 448 F.3d 1357, 1366, 79 USPQ2d 1001, 1007 (Fed. Cir. 2006); see also Capon v. Eshhar, 418 F.3d at 1358, 76 USPQ2d at 1084 ("The Board erred in holding that the specifications do not meet the written description requirement because they do not reiterate the structure or formula or chemical name for the nucleotide sequences of the claimed chimeric genes" where the genes were novel combinations of known DNA segments.). However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
Describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described.").
The claims are drawn to, at least, 2-chain chimeric antigen receptor, and encoding nucleic acids, whose structural antigen binding domains include a “vH fragment” and a “vL fragment”, the transmembrane domains comprise a CD3z transmembrane domain “or functional portion of” and a CD3z chain “or fragment thereof.”
Thus, the claims are drawn to a large genus of nucleic acids encoding a large genus of polypeptides encoding a 2-chain heterodimeric chimeric peptide receptor comprising multiple individual fragments/portions, wherein each individual fragment/portion must function not only within its individual chain, but must further function when the 2-chains are co-expressed and form the heterodimeric receptor.
CD3z chains of the claimed zSIRs are defined as “as the protein provided as GenBank Accession No. BAG36664.1, or the equivalent residues from a non-human species…is defined as the amino acid residues from the cytoplasmic domain of the zeta chain, or functional derivatives thereof, that are sufficient to functionally transmit an initial signal necessary for T cell activation.” Paragraph [0128]. Thus, a “CD3z chain” includes the entire cytoplasmic domain, or functional derivatives thereof, that are sufficient to functionally transmit an initial signal necessary for T cell activation.
The vH fragment and vL fragment are disclosed as a smaller portion of an antibody fragment. “The term ‘antibody fragment’ refers to at least one portion of an antibody, that retains the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing/destabilizing, spatial distribution) an epitope of an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab', … single domain antibodies such as sdAb (either vL or vH).” Paragraph [0040]. There is no requirement that a “vH fragment” is equivalent to a “vH domain” or that a “vL fragment” is equivalent to a “vL domain.” Thus, a “vH fragment” and a “vL fragment” may be smaller portions of a vH or vL domain, but retain the ability to bind the target antigen of the parent antibody.
The scope of a “functional portion” or “fragment” of a domain within a zSIR is defined as “The term ‘functional portion’ when used in reference to, e.g., a zSIR refers to any part or fragment of a polypeptide, e.g., the zSIR, which part or fragment retains the biological activity of the desired molecule, e.g., of the zSIR, of which it is a part (e.g., the parent zSIR). For example, functional portions encompass those parts of a zSIR that retain the ability to recognize target cells, or detect, treat, or prevent a disease, to a similar extent, the same extent, or to a higher extent, as the parent zSIR. In reference to the parent zSIR, the functional portion can comprise, for instance, about 10%, 25%, 30%, 50%, 68%, 80%, 90%, 95%, or more, of the parent zSIR.” Paragraph [0095].
Thus, the specification discloses “fragments” and “functional portions” of a specific domain allow for
1) smaller peptide segments of a domain, wherein the smaller segments have 100% identity to the corresponding segment of the parent sequence, and retain the function of the parent peptide domain; and
2) peptides with as little as 10% homology to the parent peptide domain, so long as the peptides retain the function of the parent peptide domain.
Thus, the zSIRs (nucleic acids or peptides encoded by) of the independent claims encompass, at least:
a first protein chain comprising a vH domain fragment from an antibody operably linked to a CD3z intracellular domain comprising a CD3z transmembrane domain; and
a second protein chain comprising a vL domain fragment from the antibody operably linked to a CD3z intracellular domain comprising a CD3z transmembrane domain,
wherein expression of the first protein chain and the second protein chain form heterodimers, and wherein the vH domain fragment and/or vL domain fragment are able to bind the target antigen of the parent antibody.
There are many examples of functional zSIRs within the specification. However, there is no disclosure as how the functional zSIRs disclosed in the specification were generated. In addition, the specification provides many tables disclosing many individual protein domains that may be used together to generate a chimeric receptor. However, there is no teaching in the specification regarding how the established zSIRs, and their individual domains (vH fragment, vL fragment, CD3z chain), can be further modified (by fragmentation or reduction in homology) that would allow the domains to retain their domain function and still allow the two-chains of the zSIR to function as a heterodimer receptor. There is no disclosure showing modification of a functional vH fragment and vL fragment pair that would allow such modification to retain binding to its target antigen and retain the ability to form a heterodimer. There is no disclosure showing modification of a functional CD3z chain intracellular signaling domain that would allow such modification to retain its ability to form a heterodimer and functionally transmit an initial signal necessary for T cell activation. Applicant provides no guidance for identifying a functional portion or fragment of a domain within a zSIR except by trial-and-error screening [0622]-[0633].
In addition, there is no art-recognized correlation between modification of individual domains within a chimeric immune receptor and their ability to retain the function of the parent domain, based on which those of ordinary skill in the art could predict which amino acids can vary, or which minimal fragments can be utilized to maintain individual domain and overall chimeric receptor function.
Claims 44-55, 57-61 are included in the rejection because they depend from a rejected claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 44-45, 47, 50-56, 58, 59, 60, 62, are rejected under 35 U.S.C. 103 as being unpatentable over WO99/57268 to Lawson in view of US Patent Application Publication No. 2012/0134970 to Yang, of record.
With regard to claims 1, 56 and 62 Lawson discloses chimeric receptors, and nucleic acids encoding, comprising two or more polypeptide chains each of which contains an extracellular ligand association domain attached to a signaling domain through a transmembrane and optionally one or more spacer domains. The ligand association domains are capable of acting cooperatively with each other in the presence of ligand to form a ligand binding site (Page 2, lines 20-26). Lawson discloses in binding to the ligand each association domain moves to form a ligand binding site and in so doing establishes a close spatial proximity of the intracellular domains which form the C-terminal regions of the polypeptide chains which form a heterodimeric chimeric receptor(page 4, lines 21-29). Lawson discloses the chimeric receptor contains two independent polypeptide chains, wherein one of the chains preferably has a ligand association domain which is a VH domain or a fragment thereof, and the other has a ligand association domain which is a VL domain or a fragment thereof, from the same antibody (page 7, lines 30-35, page 4, lines 5-7).
Lawson discloses the transmembrane domain is all or part of CD3z (page 5, lines 31-36; claim 7) and each intracellular signaling domain comprises “all or part of the zeta” sequence, i.e. CD3zeta (page 5, lines 5-8, claim 6). Upon binding to ligand, the two chains of the chimeric receptor transmit signal into the cell (1page 1, 16, page 2, lines 21-36, page 4, line 31- page 5, line 8; page 5, lines 23-30). Lawson discloses when introduced into effector cells, such as T-cells (page 9, lines 15-21; page 10, lines 30-35).
Thus, Lawson discloses chimeric receptors comprising a first protein chain comprising a vH domain fragment from an antibody operably linked to a CD3z intracellular domain comprising a CD3z transmembrane domain; and a second protein chain comprising a vL domain fragment from the antibody operably linked to a CD3z intracellular domain comprising a CD3z transmembrane domain, wherein expression of the first protein chain and the second protein chain form heterodimers, and wherein the vH domain fragment and/or vL domain fragment are able to bind the target antigen of the parent antibody.
However, Lawson does not reduce the receptors to practice.
Yang discloses encoding two highly homologous chimeric immune receptors in a cell paragraphs, wherein the homology of the nucleic acids coding sequences of the receptors is codon optimized to decrease homology, thereby reducing recombination events which would reduce expression (paragraphs [0006]-[0009]). Yang discloses the receptors each comprise a CD3z transmembrane and intracellular signaling domain (paragraph [0030], [0043], [0047]; FIG 8).
It would have been obvious to combine the disclosure of Lawson with the disclosure of Yang. A skilled artisan would have been motivated to combine the two because Yang discloses its system is useful to expressing two highly homologous chimeric immune receptors. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as the elements of the claimed heterodimeric receptor was known, and expressing multiple chains of a chimeric immune receptor was known at the time.
With regard to claims 44 and 58, Lawson discloses the intracellular domains can further include CD28 (page 5, lines 31-36). Yang discloses intracellular domains of chimeric receptors can include CD28 domains which provide co-stimulatory function (paragraph [0162],[0177]).
With regard to claims 45 and 59, as noted in the Claim section above, the claim as written only requires a sequence comprising a dimer disclosed in SEQ ID NOs. 4064, 4066, 4075 or 4076. Lawson does not disclose the CD3z used therein. However, Yang’s SEQ ID NO: 2 discloses at least two contiguous dimers with each of the claimed amino acid sequences:
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With regard to claim 47, Lawson discloses optional peptide linkers, including constant domains from antibodies, can be between the VH and TM domains, and the VL and TM domains of the receptors (page 2, lines page 6, lines 14-36).
With regard to claims 50, and 60 Lawson discloses the antigen binding domains of the receptor bind disease associated antigens, (page 3 lines 25-page 4, lines 4), but does not disclose targeting CD19. However, Yang disclose chimeric antigen receptors can target CD19 (paragraph [0149]).
With regard to claim 51, Lawson discloses the receptors are heterodimeric.
With regard to claim 52, Lawson discloses the nucleic acids are encoded on a vector. Including adenoviral and retroviral vectors (page 8, lines 13-36).
With regard to claim 53, Lawson discloses recombinant cells comprising the nucleic acids encoding the receptors, such as T-cells (page 9, lines 15-21; page 10, lines 30-35).
With regard to claims 54-55, Lawson does not disclose wherein the recombinant cells are formulated as pharmaceutical compositions. However, Yang discloses cells comprising the nucleic acids encoding the CIRs are used in methods of immunotherapy, including in methods of treating cancer (paragraphs [0108]- [0109], [0149], [0157], [0171]-[0176], [0206], [0210]), formulated as pharmaceutical compositions (paragraphs [0242]-[0244]).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633