DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Upon further consideration, the Restriction requirement mailed 10/21/2025 is withdrawn. Claims 1-7 and 10-15 are currently under consideration.
Priority
The instant application is a 371 of PCT/CN2021/109864 filed 07/30/2021 and claims foreign priority to CN202010760960.3 filed 07/31/2020.
A translated copy of CN202010760960.3 has not been filed. Therefore, it is not clear if the foreign priority document has adequate support for the instant claims.
Claim Objections
Claims 3-7, 10, and 12-15 are objected to because of the following informalities:
Claim 3 should recite the term “wherein” after the semicolon but before the phrase “the amino acid sequence” in line 3.
Claim 5 recites the phrase “is inserted with” where it should recite the term “comprises” in line 1. Claim 5 should also recite the term “wherein” after the comma but before the phrase “expression cassette” in line 2 and after the comma but before the phrase “the intracellular signaling molecule” in line 4.
Claim 6 recites the limitation “wherein the cell expressing a chimeric antigen receptor is obtained by transfection of the expression vector according to claim 5 by a host cell” where it should recite “wherein the cell expressing a chimeric antigen receptor is obtained by transfecting a host cell with the expression vector according to claim 5
Claim 15 should recite the term “wherein” after the semicolon but before the phrase “the amino acid sequence” in line 4.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Written Description
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 1-7 and 10-15 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 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to a truncated body of IL7R
α
, wherein the amino acid sequence of the truncated body of IL7R
α
is a sequence shown in SEQ ID NO. 1; a nucleic acid; a fusion protein; and a fusion nucleic acid; an expression; a cell; and a pharmaceutical composition.
It is noted that claim 12 limits the fusion proteins to those that bind CD44 and/or CD133.
The Applicant has only disclosed a single species of truncated IL7R
α
consisting of SEQ ID NO: 1 (e.g. see [0023]-[0025]). The Applicant has also only disclosed a single species of fusion protein consisting of an anti-CD44 single-chain antibody, an anti-CD 133 single-chain antibody, a CD28, a truncated body of IL7Rα, and a CD3 (e.g. see SEQ ID NO: 3 and [0031]).
It is noted that claim 1 recites that the amino acid sequence of the truncated body of IL7R
α
is a sequence shown in SEQ ID NO. 1. Therefore, when given the broadest reasonable interpretation in light of specification, the truncated IL7R
α
of the instant invention is defined broadly to be any truncated IL7R
α
with an amino acid sequence that is at least two consecutive amino acids of SEQ ID NO: 1.
This also applies to claims 11, 13, and 14 which recite “wherein the nucleic acid has a nucleotide sequence shown in SEQ ID NO. 2,” “wherein the fusion protein has an amino acid sequence shown in SEQ ID NO. 3,” and “wherein the fusion nucleic acid has a nucleotide sequence shown in SEQ ID NO. 4,” respectively. Similarly to claim 1, when given the broadest reasonable interpretation in light of specification, the nucleic acids of claims 11 and 14 and fusion protein of claim 13 are defined broadly to be any nucleic/amino acid sequence that is at least two consecutive nucleotides of SEQ ID NOs: 2-4, respectively.
Furthermore, when given the broadest reasonable interpretation in light of specification, the fusion protein of claim 12 is defined broadly to be any fusion protein that comprises an antigen binding domain that comprises any anti-CD44 single-chain antibody and/or any anti-CD133 single-chain antibody and an intracellular signaling domain that comprises the truncated body of IL7Rα.
It is noted that claim 12 (or any dependent claim thereof) does not indicate any specific structure for the genera of anti-CD44 or anti-CD133 single chain antibodies as claimed.
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 (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). 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.”
Regarding the anti-CD44 or anti-CD133 single chain antibodies, artisans are well aware that knowledge of a given antigen (for instance CD44 or CD133) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen, as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection).
Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
This applies to the instant invention which is drawn to a genus of anti-CD44 and/or a genus of anti-CD133 single chain antibodies.
As noted above, the Applicant has disclosed only a single species of truncated IL7R
α
(SEQ ID NO: 1) and a single species of fusion protein consisting of an anti-CD44 single-chain antibody, an anti-CD 133 single-chain antibody, a CD28, a truncated body of IL7Rα, and a CD3 (e.g. see SEQ ID NO: 3 and [0031]). Such a disclosure does not serve to provide sufficient written description of the claimed genus of truncated IL7R
α
that is a sequence shown in SEQ ID NO. 1 (i.e. at least two consecutive amino acids of SEQ ID NO: 1) or genus of fusion proteins that comprise an antigen binding domain that comprises any anti-CD44 single-chain antibody and/or any anti-CD133 single-chain antibody and an intracellular signaling domain that comprises the truncated body of IL7Rα. Further, the disclosure does not identify any specific structural features or combination of features which give rise to the function of binding to CD44 and/or CD133. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited fusion proteins that bind CD44 and/or CD133 which gives rise to their functional activity. Ultimately, identifying a fusion protein simply on the basis of what it binds rather than by identifying the sequence/structure, namely the CDRs, of the fusion protein in question is generally insufficient to provide written description of the in question.
Ultimately, there is insufficient written description for the breadth of truncated IL7R
α
that are any two or more consecutive amino acids of SEQ ID NO: 1 and breadth of fusion proteins that comprise an antigen binding domain that comprises any anti-CD44 single-chain antibody and/or any anti-CD133 single-chain antibody. Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of truncated IL7R
α
or fusion proteins encompassed by the claims at the time the instant application was filed.
As noted above this logic also applies to claims 11, 13, and 14 which recite “wherein the nucleic acid has a nucleotide sequence shown in SEQ ID NO. 2,” “wherein the fusion protein has an amino acid sequence shown in SEQ ID NO. 3,” and “wherein the fusion nucleic acid has a nucleotide sequence shown in SEQ ID NO. 4,” respectively. Similarly to claim 1, when given the broadest reasonable interpretation in light of specification, the nucleic acids of claims 11 and 14 and fusion protein of claim 13 are defined broadly to be any nucleic/amino acid sequence that is at least two consecutive nucleotides of SEQ ID NOs: 2-4, respectively.
Amending claim 1 to recite “A truncated body of IL7R
α
, wherein the amino acid sequence of the truncated body of IL7R
α
is SEQ ID NO. 1,” claim 11 to recite “wherein the nucleic acid comprises SEQ ID NO. 2,” claim 12 to recite all six CDR sequences of the anti-CD44 and anti-CD133 single chain antibodies, and claim 14 to recite “wherein the fusion nucleic acid comprises SEQ ID NO. 4” would obviate this part of the rejection.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 11, 13, and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kong (WO 2020/050667, published 3/12/2020, claimed priority to 9/5/2018) as evidenced by Kong (US 20220387503).
Kong (WO 2020/050667) is in Korean. Kong (US 20220387503) is the national stage under 35 USC 371 of the PCT/KR2019/011516 that is published as Kong (WO 2020/050667). Therefore, Kong (US 20220387503) is deemed to be the English translation of Kong (WO 2020/050667). Thus, the rejection is based on the content of Kong (US 20220387503).
Kong teaches a chimeric antigen receptor which comprises a part of IL-7Rα, wherein the part of IL-7Rα is SEQ ID NO: 15 (e.g. see claim 5). It is noted that Kong’s SEQ ID NO: 15 is identical to instant SEQ ID NO: 1. See sequence alignment below (Qy: instant SEQ ID NO:1, Db: the prior art sequence).
Query Match 100.0%; Score 349; DB 1; Length 95;
Best Local Similarity 100.0%;
Matches 64; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 60
Qy 61 QDTF 64
||||
Db 61 QDTF 64
It is noted that a chimeric antigen receptor is a fusion protein. Kong also teaches that their CAR comprises an antigen binding domain; a transmembrane domain; and costimulatory and cytoplasmic (or intracellular) signaling domains, wherein the intracellular signaling domain comprises part of IL-7Rα as SEQ ID NO: 15 (e.g. see [0047]). Kong also teaches that their invention also relates to a CAR expression vector which includes a nucleic acid encoding the CAR which comprises nucleic acids encoding the antigen binding domain and intracellular signaling domains including SEQ ID NO: 15 (e.g. see [0047]).
Kong also teaches that CAR-encoding vectors were prepared such that Phoenix-Ampho and Phoenix-Eco cells were transiently transfected with the retroviral expression vector prepared in Example 1, and then, cell-free vector stocks were prepared from the transfected Phoenix-Ampho and Phoenix-Eco cells by transfecting PG13 cells (e.g. see [0091]). These CARs include those that express SEQ ID NO: 15. The CAR expression vectors were isolated from the PG13 cells and were use to transduce T cells ([0094]).
Kong also teaches that their CAR T-cells can be effectively used in the field of customized cancer treatment (e.g. see [0164]). Kong also teaches that a method for treating cancer using CAR-T cells includes injecting patients with the CAR-T cells (e.g. see [0013]). It is noted that in order for a CAR-T cell to be injected or administered to a patient it, would need to be comprises in a pharmaceutical composition. Kong teaches anticancer agent comprising the CAR-T and a pharmaceutically acceptable additive (e.g. see [0053]).
Kong also teaches an expression vector that comprises a fusion nucleic acid which encodes a fusion protein comprising an antigen binding domain, a transmembrane domain, and an intracellular signaling domain that are sequentially linked, wherein the intracellular signaling domain may comprise SEQ ID NO: 15 (e.g. see Fig. 1).
Regarding claims 11, 13, and 14, which recite “wherein the nucleic acid has a nucleotide sequence shown in SEQ ID NO. 2,” “wherein the fusion protein has an amino acid sequence shown in SEQ ID NO. 3,” and “wherein the fusion nucleic acid has a nucleotide sequence shown in SEQ ID NO. 4,” respectively; as noted above, when given the broadest reasonable interpretation in light of specification, the nucleic acids of claims 11 and 14 and fusion protein of claim 13 are defined broadly to be any nucleic/amino acid sequence that is at least two consecutive nucleotides of SEQ ID NOs: 2-4, respectively.
Therefore, given that Kong’s SEQ ID NO: 15 is identical to instant SEQ ID NO: 1, an amino acid comprising instant SEQ ID NO: 1, such as the Kong’s CAR, would comprise at least two consecutive amino acids of instant SEQ ID NO: 3.
Furthermore, a nucleic acid encoding this amino acid sequence would comprise at least two consecutive nucleotides of instant SEQ ID NOs: 2 and 4. For example, the truncated IL-7Rα begins with an N-terminal lysine which can only be encoded by the nucleotide codons AAA or AAG and therefore, Kong’s a nucleic acid encoding SEQ ID NO: 15 must include one of these codons. Given that both instant SEQ ID NOs: 2 and 4 comprise at least the nucleotide sequence “AA” as part of a lysine-encoding nucleotide codons, Kong’s nucleic acid encoding SEQ ID NO: 15 would necessarily have at least two consecutive nucleotides of SEQ ID NOs: 2 and 4.
Therefore the reference teachings anticipate the instant claims.
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.
Claims 1, 5-7, 10, and 15 are rejected under 35 U.S.C. 103 as being unpatentable Kong (WO 2020/050667, published 3/12/2020, claimed priority to 9/5/2018) as evidenced by Kong (US 20220387503) in view of Renaud-Gabardos et al. 2015 (World J Exp Med. 5(1): 11-20).
The teachings of Kong are outlined in the 102 rejection above.
Kong does not teach that an IRES element encoding sequence is inserted between the first nucleic acid fragment encoding an antigen binding molecule and the second nucleic acid fragment encoding an intracellular signaling molecule.
Renaud-Gabardos et al. teach that internal ribosome entry sites (IRESs), RNA elements naturally present in the 5’ untranslated regions of a few mRNAs, constitute a powerful tool to co-express several genes of interest (e.g. see Abstract). IRESs are translational enhancers allowing the translational machinery to start protein synthesis by internal initiation. This feature allows for the design of multi-cistronic vectors expressing several genes from a single mRNA (e.g. see Abstract). IRESs have been used to generate transgene co-expression under the control of a single promoter (e.g. see page 12, right column, third paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Kong to incorporate the teachings of Renaud-Gabardos et al. to include that an IRES element encoding sequence is inserted between the first nucleic acid fragment encoding an antigen binding molecule and the second nucleic acid fragment encoding an intracellular signaling molecule. This is because IRESs constitute a powerful tool to co-express several genes of interest.
Given that IRESs are translational enhancers that allow for the design of multi-cistronic vectors expressing several genes from a single mRNA and that they have been used to generate transgene co-expression under the control of a single promoter as disclosed by Renaud-Gabardos et al.; it would have been obvious to a skilled artisan, with the goal of translating the antigen binding molecule and intracellular signaling molecule of the CAR separately but from a single expression vector under the control a single promoter, to include an IRES element encoding sequence between the nucleic acid fragment encoding the antigen binding molecule and the nucleic acid fragment encoding the intracellular signaling molecule of Kong’s CAR-encoding expression vector with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1, 3, and 12 are rejected under 35 U.S.C. 103 as being unpatentable Kong (WO 2020/050667, published 3/12/2020, claimed priority to 9/5/2018) as evidenced by Kong (US 20220387503) in view of Wang et al. 2018 (Oncoimmunology, 7(7); e1440169, 1-13).
The teachings of Kong are outlined in the 102 rejection above. Kong teaches that the antigen binding domain in the CAT polypeptide can be changed to target various cancer antigens as necessary (e.g. see [0054]). Kong further teach that the CAR-T cells have excellent expression rate and persistence anti-tumor effect in human body with improved therapeutic effect against solid cancer (e.g. see [0058]). Kong also teach single-chain antibody-based antigen binding domains (e.g. see SEQ ID NOs: 3, 7, and 33).
The teachings of Kong differ from the instant invention by not describing an anti-CD133 single-chain antibody as the antigen binding domain in the CAR.
Wang et al. teach that CD133 is expressed by cancer stem cells of various epithelial cell origins and is an attractive therapeutic target (e.g. see Abstract). Wang et al. also teach an autologous chimeric antigen receptor-modified T-cells directed to CD133 (CART-133) which were able to eliminate CD133+ cells. Wang et al. also teach the feasibility, controllable toxicities, and effective activity of CART-133 transfer for treating patients with CD133-postive and late-stage metastasis malignancies (e.g. see Abstract).
Wang et al. also teach that adoptive immunotherapy with anti-CD133 CAR-modified T cells is a feasible and possibly effective treatment (e.g. see page 13, left column, second paragraph). Patients can achieve longer stable survival time or even partial remission of disease after CART-133 cell therapy. Hepatocellular carcinoma patients with lower tumor burden or who maintain an early stage of tumor may have a favorable clinical response even with repeated CART-133 monotherapy. Wang et al. teach that their data will facilitate subsequent clinical trials to further augment the expansion, function, and persistence of CART-133 cells in the future (e.g. see page 13, left column, second paragraph).
Wang et al, also teach that their CART-133 contains an anti-CD133 scFv (e.g. see page 2, paragraph spanning the left and right columns).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Kong to incorporate the teachings of Wang et al. to include that the antigen binding domain of the fusion protein comprises an anti-CD133 single-chain antibody. This is because CD133 is an attractive therapeutic target and can be used in CAR-T for treating last-stage metastasis malignancies as disclosed by Wang et al.
Given that CD133 is expressed by cancer stem cells of various epithelial cell origins and is an attractive therapeutic target for CAR-T therapy and in view of the excellent expression rate and persistence of the CAR-T cell comprising the truncated IL7Rα as intracellular signaling domain disclosed by Kong, ; it would have been obvious to a skilled artisan to substitute the antigen binding domain of Kong’s CAR T cell with an anti-CD133 antigen binding domain with a reasonable expectation of success. Such a CAR-T comprising anti-CD133 single chain and the truncated IL7Rα as intracellular signaling domain would be expected to have the benefit of excellent expression rate and persistent anti-tumor effects.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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 1-4 and 11-14 are provisionally rejected on the ground of nonstatutory double patenting (NSDP) as being unpatentable over claims 13 and 14 of U.S. Application No. 18/018,778 (the ‘778 Application) in view of Kong (WO 2020/050667, published 3/12/2020, claimed priority to 9/5/2018) as evidenced by Kong (US 20220387503).
The instant claims are drawn to a truncated body of IL7R
α
, wherein the amino acid sequence of the truncated body of IL7R
α
is a sequence shown in SEQ ID NO. 1; a nucleic acid; a fusion protein; and a fusion nucleic acid.
The claims in the ‘778 Application are drawn to a fusion protein that has an amino acid sequence shown in any of SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, or SEQ ID NO. 6; and a fusion nucleic acid that has a nucleotide sequence shown in any of SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9, or SEQ ID NO. 10.
It is noted that SEQ ID NOs: 4 and 6 of the ‘778 Application are CAR constructs that comprise a truncated body of IL7R
α
that is identical to instant SEQ ID NO: 1. See sequence alignments below. SEQ ID NOs: 3 and 5 of the ‘778 Application do not comprise a truncated body of IL7R
α
. It is further noted that SEQ ID NOs: 7-10 of the ‘778 Application are nucleic acid sequences encoding SEQ ID NOs: 3-6, respectively (e.g. see [0044]-[0052]).
It is also noted that SEQ ID NOs: 8 and 10 of the ‘778 Application comprise or are identical to instant SEQ ID NOs: 2 and 4. See sequence alignments below.
Alignment of SEQ ID NO: 4 of the ‘778 Application and instant SEQ ID NO: 1:
Query Match 16.9%; Score 505; DB 1; Length 95;
Best Local Similarity 100.0%;
Matches 95; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 355 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 414
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 60
Qy 415 QDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQ 449
|||||||||||||||||||||||||||||||||||
Db 61 QDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQ 95
Alignment of SEQ ID NO: 6 of the ‘778 Application and instant SEQ ID NO: 1:
Query Match 11.5%; Score 505; DB 1; Length 95;
Best Local Similarity 100.0%;
Matches 95; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 355 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 414
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 60
Qy 415 QDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQ 449
|||||||||||||||||||||||||||||||||||
Db 61 QDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQ 95
Alignment of SEQ ID NO: 8 of the ‘778 Application and instant SEQ ID NO: 2:
Query Match 16.9%; Score 285; DB 1; Length 285;
Best Local Similarity 100.0%;
Matches 285; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1063 AAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAA 1122
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAA 60
Qy 1123 CACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTG 1182
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTG 120
Qy 1183 GACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTG 1242
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTG 180
Qy 1243 CAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAAT 1302
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 CAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAAT 240
Qy 1303 CAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAG 1347
|||||||||||||||||||||||||||||||||||||||||||||
Db 241 CAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAG 285
Alignment of SEQ ID NO: 10 of the ‘778 Application and instant SEQ ID NO: 2:
Query Match 11.2%; Score 285; DB 1; Length 285;
Best Local Similarity 100.0%;
Matches 285; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1063 AAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAA 1122
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAA 60
Qy 1123 CACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTG 1182
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTG 120
Qy 1183 GACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTG 1242
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTG 180
Qy 1243 CAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAAT 1302
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 CAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAAT 240
Qy 1303 CAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAG 1347
|||||||||||||||||||||||||||||||||||||||||||||
Db 241 CAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAG 285
Alignment of SEQ ID NO: 8 of the ‘778 Application and instant SEQ ID NO: 4:
Query Match 100.0%; Score 1683; DB 1; Length 2466;
Best Local Similarity 100.0%;
Matches 1683; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 784 CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTC 843
Qy 61 TCCTGCAAGGCTTCTGGTTACACCTTTACCGACTTTGAAATGCACTGGGTGCGACAGGCC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 844 TCCTGCAAGGCTTCTGGTTACACCTTTACCGACTTTGAAATGCACTGGGTGCGACAGGCC 903
Qy 121 CCTGGACAAGGGCTTGAGTGGATGGGAGATATTGATCCTGGAACTGGTGATACTGCCTAC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 904 CCTGGACAAGGGCTTGAGTGGATGGGAGATATTGATCCTGGAACTGGTGATACTGCCTAC 963
Qy 181 AATCTGAAGTTCAAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 964 AATCTGAAGTTCAAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC 1023
Qy 241 ATGGAGCTGAGGAGCCTGAGGTCTGACGACACGGCCGTGTATTACTGTGCGTTGGGGGCC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1024 ATGGAGCTGAGGAGCCTGAGGTCTGACGACACGGCCGTGTATTACTGTGCGTTGGGGGCC 1083
Qy 301 TTTGTTTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGCAGTACTAGCGGTGGT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1084 TTTGTTTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGCAGTACTAGCGGTGGT 1143
Qy 361 GGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGATGTTGTGATGACTCAGTCTCCA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1144 GGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGATGTTGTGATGACTCAGTCTCCA 1203
Qy 421 CTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGT 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1204 CTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGT 1263
Qy 481 CTTGCAAACAGTTATGGGAACACCTATTTGTCTTGGTACCTGCAGAAGCCAGGGCAGTCT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1264 CTTGCAAACAGTTATGGGAACACCTATTTGTCTTGGTACCTGCAGAAGCCAGGGCAGTCT 1323
Qy 541 CCACAGCTCCTGATCTATGGGATTTCCAACAGATTTTCTGGGGTCCCTGACAGGTTCAGT 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1324 CCACAGCTCCTGATCTATGGGATTTCCAACAGATTTTCTGGGGTCCCTGACAGGTTCAGT 1383
Qy 601 GGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGACGTT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1384 GGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGACGTT 1443
Qy 661 GGGGTTTATTACTGCTTACAAGGTACACATCAGCCGTACACGTTTGGCCAGGGGACCAAG 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1444 GGGGTTTATTACTGCTTACAAGGTACACATCAGCCGTACACGTTTGGCCAGGGGACCAAG 1503
Qy 721 CTGGAGATCAAAACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCC 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1504 CTGGAGATCAAAACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCC 1563
Qy 781 TCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCAT 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1564 TCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCAT 1623
Qy 841 ACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1624 ACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 1683
Qy 901 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAGGAGTAAGAGGAGCAGGCTC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1684 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAGGAGTAAGAGGAGCAGGCTC 1743
Qy 961 CTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTAC 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1744 CTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTAC 1803
Qy 1021 CAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAAAAAAAGGATTAAGCCT 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1804 CAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAAAAAAAGGATTAAGCCT 1863
Qy 1081 ATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAACACCTTTGTAAGAAACCA 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1864 ATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAACACCTTTGTAAGAAACCA 1923
Qy 1141 AGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTGGACTGCCAGATTCATAGG 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1924 AGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTGGACTGCCAGATTCATAGG 1983
Qy 1201 GTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTGCAAGATACGTTTCCTCAG 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1984 GTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTGCAAGATACGTTTCCTCAG 2043
Qy 1261 CAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAATCAAGAAGAAGCATATGTC 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2044 CAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAATCAAGAAGAAGCATATGTC 2103
Qy 1321 ACCATGTCCAGCTTCTACCAAAACCAGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2104 ACCATGTCCAGCTTCTACCAAAACCAGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 2163
Qy 1381 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAG 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2164 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAG 2223
Qy 1441 TACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGA 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2224 TACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGA 2283
Qy 1501 AAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTAT 1560
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2284 AAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTAT 2343
Qy 1561 AGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAG 1620
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2344 AGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAG 2403
Qy 1621 GGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCT 1680
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2404 GGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCT 2463
Qy 1681 CGG 1683
|||
Db 2464 CGG 2466
Alignment of SEQ ID NO: 10 of the ‘778 Application and instant SEQ ID NO: 4:
Query Match 66.4%; Score 1683; DB 1; Length 2466;
Best Local Similarity 100.0%;
Matches 1683; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 784 CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTC 843
Qy 61 TCCTGCAAGGCTTCTGGTTACACCTTTACCGACTTTGAAATGCACTGGGTGCGACAGGCC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 844 TCCTGCAAGGCTTCTGGTTACACCTTTACCGACTTTGAAATGCACTGGGTGCGACAGGCC 903
Qy 121 CCTGGACAAGGGCTTGAGTGGATGGGAGATATTGATCCTGGAACTGGTGATACTGCCTAC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 904 CCTGGACAAGGGCTTGAGTGGATGGGAGATATTGATCCTGGAACTGGTGATACTGCCTAC 963
Qy 181 AATCTGAAGTTCAAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 964 AATCTGAAGTTCAAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC 1023
Qy 241 ATGGAGCTGAGGAGCCTGAGGTCTGACGACACGGCCGTGTATTACTGTGCGTTGGGGGCC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1024 ATGGAGCTGAGGAGCCTGAGGTCTGACGACACGGCCGTGTATTACTGTGCGTTGGGGGCC 1083
Qy 301 TTTGTTTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGCAGTACTAGCGGTGGT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1084 TTTGTTTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGCAGTACTAGCGGTGGT 1143
Qy 361 GGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGATGTTGTGATGACTCAGTCTCCA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1144 GGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGATGTTGTGATGACTCAGTCTCCA 1203
Qy 421 CTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGT 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1204 CTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGT 1263
Qy 481 CTTGCAAACAGTTATGGGAACACCTATTTGTCTTGGTACCTGCAGAAGCCAGGGCAGTCT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1264 CTTGCAAACAGTTATGGGAACACCTATTTGTCTTGGTACCTGCAGAAGCCAGGGCAGTCT 1323
Qy 541 CCACAGCTCCTGATCTATGGGATTTCCAACAGATTTTCTGGGGTCCCTGACAGGTTCAGT 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1324 CCACAGCTCCTGATCTATGGGATTTCCAACAGATTTTCTGGGGTCCCTGACAGGTTCAGT 1383
Qy 601 GGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGACGTT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1384 GGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGACGTT 1443
Qy 661 GGGGTTTATTACTGCTTACAAGGTACACATCAGCCGTACACGTTTGGCCAGGGGACCAAG 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1444 GGGGTTTATTACTGCTTACAAGGTACACATCAGCCGTACACGTTTGGCCAGGGGACCAAG 1503
Qy 721 CTGGAGATCAAAACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCC 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1504 CTGGAGATCAAAACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCC 1563
Qy 781 TCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCAT 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1564 TCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCAT 1623
Qy 841 ACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1624 ACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 1683
Qy 901 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAGGAGTAAGAGGAGCAGGCTC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1684 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAGGAGTAAGAGGAGCAGGCTC 1743
Qy 961 CTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTAC 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1744 CTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTAC 1803
Qy 1021 CAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAAAAAAAGGATTAAGCCT 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1804 CAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAAAAAAAGGATTAAGCCT 1863
Qy 1081 ATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAACACCTTTGTAAGAAACCA 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1864 ATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAACACCTTTGTAAGAAACCA 1923
Qy 1141 AGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTGGACTGCCAGATTCATAGG 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1924 AGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTGGACTGCCAGATTCATAGG 1983
Qy 1201 GTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTGCAAGATACGTTTCCTCAG 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1984 GTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTGCAAGATACGTTTCCTCAG 2043
Qy 1261 CAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAATCAAGAAGAAGCATATGTC 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2044 CAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAATCAAGAAGAAGCATATGTC 2103
Qy 1321 ACCATGTCCAGCTTCTACCAAAACCAGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2104 ACCATGTCCAGCTTCTACCAAAACCAGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 2163
Qy 1381 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAG 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2164 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAG 2223
Qy 1441 TACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGA 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2224 TACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGA 2283
Qy 1501 AAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTAT 1560
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2284 AAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTAT 2343
Qy 1561 AGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAG 1620
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2344 AGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAG 2403
Qy 1621 GGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCT 1680
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2404 GGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCT 2463
Qy 1681 CGG 1683
|||
Db 2464 CGG 2466
The claims in the ‘778 Application differ from the instant invention by not reciting only the CAR constructs of SEQ ID NOs: 4 and 6 and their corresponding nucleic acids (SEQ ID NOs: 8 and 10).
The teachings of Kong are outlined in the 102 rejection above. Kong also teaches that in order to induce a cytokine signal in an antigen-dependent manner during stimulation of cancer antigens, a cleaved (or truncated) cytoplasmic domain of interleukin-7 receptor-α (IL7Rα) in addition to the CD3ζ signaling domain and a 4-1BB costimulatory domain was added to a CAR gene so as to reduce the differentiation and exhaustion of CAR-T cells caused by CAR tonic signaling of CAR-T cells, thereby making it capable of exhibiting excellent in vivo persistence and anti-tumor effects (e.g. see [0005]).
Thus, it would be obvious to one of ordinary skill in the art modify the ‘778 Application to incorporate the teachings of Kong to specifically select the CAR constructs of the ‘778 Application that comprise a truncated body of IL7R
α
. This is because the inclusion of a cleaved (or truncated) cytoplasmic domain of IL7Rα in a CAR construct reduces the differentiation and exhaustion of CAR-T cells caused by CAR tonic signaling of CAR-T cells.
Given that the addition of a cleaved (or truncated) cytoplasmic domain of IL7Rα to the intracellular signaling domain is used to induce a cytokine signal in an antigen-dependent manner during stimulation of cancer antigens and can reduce the differentiation and exhaustion of CAR-T cells caused by CAR tonic signaling of CAR-T cells, thereby making it capable of exhibiting excellent in vivo persistence and anti-tumor effects; it would be obvious to a skilled artisan, with the goal of selecting the most efficient CAT constructs of the ‘778 Application, to specifically select SEQ ID NOs: 4 and 6 and their corresponding nucleic acids (SEQ ID NOs: 8 and 10) with a reasonable expectation of success.
It is noted that obtaining cDNA / nucleic acids from protein sequences has been routine and conventional in the art and used to make proteins of interest, including CARs of interest. For example, expression vectors can comprise polynucleotides sequences encoding amino acids, in turn CARs (e.g., CARs comprising a truncated body of IL7R
α
). Given that obtaining cDNA / nucleic acids from protein sequence sequences is routine and conventional, it would have been obvious to the ordinary artisan to obtaining cDNA to produce proteins of interest.
This applies to the instant case where it would be obvious to a skilled artisan to obtain the nucleic acid, fusion nucleic acid, expression vector of the instant invention from the CAR constructs of the ‘778 Application.
As such, the claims in the ‘778 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5-7, 10, and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 and 14 of U.S. Application No. 18/018,778 (the ‘778 Application) in view of Kong (WO 2020/050667, published 3/12/2020, claimed priority to 9/5/2018) as evidenced by Kong (US 20220387503) and Renaud-Gabardos et al. 2015 (World J Exp Med. 5(1): 11-20).
The instant claims are drawn to a truncated body of IL7R
α
, wherein the amino acid sequence of the truncated body of IL7R
α
is a sequence shown in SEQ ID NO. 1; an expression vector; a cell; and a pharmaceutical composition.
The claims in the ‘778 Application are drawn to a fusion protein that has an amino acid sequence shown in any of SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, or SEQ ID NO. 6; and a fusion nucleic acid that has a nucleotide sequence shown in any of SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9, or SEQ ID NO. 10.
It is noted that SEQ ID NOs: 4 and 6 of the ‘778 Application are CAR constructs that comprise a truncated body of IL7R
α
that is identical to instant SEQ ID NO: 1. See sequence alignments above. SEQ ID NOs: 3 and 5 of the ‘778 Application do not comprise a truncated body of IL7R
α
. It is further noted that SEQ ID NOs: 7-10 of the ‘778 Application are nucleic acid sequences encoding SEQ ID NOs: 3-6, respectively (e.g. see [0044]-[0052]).
The claims in the ‘778 Application differ from the instant invention by not reciting only the CAR constructs of SEQ ID NOs: 4 and 6 and their corresponding nucleic acids (SEQ ID NOs: 8 and 10); or that an IRES element encoding sequence is inserted between the first nucleic acid fragment encoding an antigen binding molecule and the second nucleic acid fragment encoding an intracellular signaling molecule.
The teachings of Kong are outlined in the 102 and NSDP rejections above.
Renaud-Gabardos et al. teach that internal ribosome entry sites (IRESs), RNA elements naturally present in the 5’ untranslated regions of a few mRNAs, constitute a powerful tool to co-express several genes of interest (e.g. see Abstract). IRESs are translational enhancers allowing the translational machinery to start protein synthesis by internal initiation. This feature allows for the design of multi-cistronic vectors expressing several genes from a single mRNA (e.g. see Abstract). IRESs have been used to generate transgene co-expression under the control of a single promoter (e.g. see page 12, right column, third paragraph).
Thus, it would be obvious to one of ordinary skill in the art modify the ‘778 Application to incorporate the teachings of Kong to specifically select the CAR constructs of the ‘778 Application that comprise a truncated body of IL7R
α
and to include that an IRES element encoding sequence is inserted between the first nucleic acid fragment encoding an antigen binding molecule and the second nucleic acid fragment encoding an intracellular signaling molecule. This is because the inclusion of a cleaved (or truncated) cytoplasmic domain of IL7Rα in a CAR construct reduces the differentiation and exhaustion of CAR-T cells caused by CAR tonic signaling of CAR-T cells and IRESs constitute a powerful tool to co-express several genes of interest.
Given that the addition of a cleaved (or truncated) cytoplasmic domain of IL7Rα to the intracellular signaling domain is used to induce a cytokine signal in an antigen-dependent manner during stimulation of cancer antigens and can reduce the differentiation and exhaustion of CAR-T cells caused by CAR tonic signaling of CAR-T cells, thereby making it capable of exhibiting excellent in vivo persistence and anti-tumor effects; it would be obvious to a skilled artisan, with the goal of selecting the most efficient CAT constructs of the ‘778 Application, to specifically select SEQ ID NOs: 4 and 6 and their corresponding nucleic acids (SEQ ID NOs: 8 and 10) with a reasonable expectation of success.
It is noted that obtaining cDNA / nucleic acids from protein sequences has been routine and conventional in the art and used to make proteins of interest, including CARs of interest. For example, expression vectors can comprise polynucleotides sequences encoding amino acids, in turn CARs (e.g., CARs comprising a truncated body of IL7R
α
). Given that obtaining cDNA / nucleic acids from protein sequence sequences is routine and conventional, it would have been obvious to the ordinary artisan to obtaining cDNA to produce proteins of interest.
This applies to the instant case where it would be obvious to a skilled artisan to obtain the nucleic acid, fusion nucleic acid, expression vector of the instant invention from the CAR constructs of the ‘778 Application.
Furthermore, given that IRESs are translational enhancers that allow for the design of multi-cistronic vectors expressing several genes from a single mRNA and that they have been used to generate transgene co-expression under the control of a single promoter; it would have been obvious to a skilled artisan, with the goal of translating the antigen binding molecule and intracellular signaling molecule of the CAR separately but from a single expression vector under the control a single promoter, to include an IRES element encoding sequence between the nucleic acid fragment encoding the antigen binding molecule and the nucleic acid fragment encoding the intracellular signaling molecule in an expression vector encoding ‘778 Application’s CAR constructs of SEQ ID NOs: 4 and 6.
As such, the claims in the ‘778 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4 and 11-14 are provisionally rejected on the ground of nonstatutory double patenting (NSDP) as being unpatentable over claims 13-16 and 20 of U.S. Application No. 18/018,764 (the ‘764 Application) in view of Kong (WO 2020/050667, published 3/12/2020, claimed priority to 9/5/2018) as evidenced by Kong (US 20220387503).
The instant claims are drawn to a truncated body of IL7R
α
, wherein the amino acid sequence of the truncated body of IL7R
α
is a sequence shown in SEQ ID NO. 1; a nucleic acid; a fusion protein; and a fusion nucleic acid.
The claims in the ‘764 Application are drawn to a fusion protein that has an amino acid sequence shown in any of SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7 or SEQ ID NO. 8; a fusion nucleic acid that has a nucleotide sequence shown in any of SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, or SEQ ID NO. 14; and a fusion protein comprising IL7R
α
or a truncated form thereof.
It is noted that SEQ ID NOs: 5, 7, and 8 of the ‘764 Application are CAR constructs that comprise a truncated body of IL7R
α
that is identical to instant SEQ ID NO: 1. See sequence alignments below. SEQ ID NOs: 3, 4, and 6 of the ‘764 Application do not comprise a truncated body of IL7R
α
. It is further noted that SEQ ID NOs: 9-14 of the ‘764 Application are nucleic acid sequences encoding SEQ ID NOs: 3-8, respectively.
It is also noted that SEQ ID NOs: 11, 13, and 14 of the ‘778 Application comprise or are identical to either all or part of instant SEQ ID NOs: 2 and 4. See sequence alignments below.
Alignment of SEQ ID NO: 5 of the ‘778 Application and instant SEQ ID NO: 1:
Query Match 16.9%; Score 505; DB 1; Length 95;
Best Local Similarity 100.0%;
Matches 95; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 357 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 416
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 60
Qy 417 QDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQ 451
|||||||||||||||||||||||||||||||||||
Db 61 QDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQ 95
Alignment of SEQ ID NO: 7 of the ‘778 Application and instant SEQ ID NO: 1:
Query Match 11.4%; Score 505; DB 1; Length 95;
Best Local Similarity 100.0%;
Matches 95; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 357 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 416
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 60
Qy 417 QDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQ 451
|||||||||||||||||||||||||||||||||||
Db 61 QDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQ 95
Alignment of SEQ ID NO: 8 of the ‘778 Application and instant SEQ ID NO: 1:
Query Match 8.7%; Score 505; DB 1; Length 95;
Best Local Similarity 100.0%;
Matches 95; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 616 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 675
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 KKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFL 60
Qy 676 QDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQ 710
|||||||||||||||||||||||||||||||||||
Db 61 QDTFPQQLEESEKQRLLGSNQEEAYVTMSSFYQNQ 95
Alignment of SEQ ID NO: 11 of the ‘778 Application and instant SEQ ID NO: 2:
Query Match 16.9%; Score 285; DB 1; Length 285;
Best Local Similarity 100.0%;
Matches 285; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1069 AAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAA 1128
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAA 60
Qy 1129 CACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTG 1188
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTG 120
Qy 1189 GACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTG 1248
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTG 180
Qy 1249 CAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAAT 1308
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 CAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAAT 240
Qy 1309 CAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAG 1353
|||||||||||||||||||||||||||||||||||||||||||||
Db 241 CAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAG 285
Alignment of SEQ ID NO: 13 of the ‘778 Application and instant SEQ ID NO: 2:
Query Match 11.4%; Score 285; DB 1; Length 285;
Best Local Similarity 100.0%;
Matches 285; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1069 AAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAA 1128
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAA 60
Qy 1129 CACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTG 1188
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTG 120
Qy 1189 GACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTG 1248
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTG 180
Qy 1249 CAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAAT 1308
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 CAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAAT 240
Qy 1309 CAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAG 1353
|||||||||||||||||||||||||||||||||||||||||||||
Db 241 CAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAG 285
Alignment of SEQ ID NO: 14 of the ‘778 Application and instant SEQ ID NO: 2:
Query Match 8.7%; Score 285; DB 1; Length 285;
Best Local Similarity 100.0%;
Matches 285; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1846 AAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAA 1905
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAA 60
Qy 1906 CACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTG 1965
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTG 120
Qy 1966 GACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTG 2025
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTG 180
Qy 2026 CAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAAT 2085
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 CAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAAT 240
Qy 2086 CAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAG 2130
|||||||||||||||||||||||||||||||||||||||||||||
Db 241 CAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAG 285
Alignment of SEQ ID NO: 11 of the ‘778 Application and instant SEQ ID NO: 4:
Query Match 75.8%; Score 1280.8; DB 1; Length 2466;
Best Local Similarity 85.7%;
Matches 1461; Conservative 0; Mismatches 207; Indels 36; Gaps 2;
Qy 1 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTC 60
||||| ||||||||| ||||||| | | ||| |||||||| || ||| ||
Db 784 CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTC 843
Qy 61 TCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCT 120
||||| || ||||| | |||||| | || || ||||||||||| || |||||
Db 844 TCCTGCAAGGCTTCTGGTTACACCTTTACCGACTTTGAAATGCACTGGGTGCGACAGGCC 903
Qy 121 CCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATTCTAT 180
|| || | ||||| |||||| ||| || ||| || || ||| |||
Db 904 CCTGGACAAGGGCTTGAGTGGATGGGAGATATTGATCCTGGAACTGGTGATACTGCCTAC 963
Qy 181 GCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT 240
| |||||| || ||||||| ||| ||||| |||| || ||| ||
Db 964 AATCTGAAGTTCAAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC 1023
Qy 241 CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGGAGAAGT 300
|| | ||| |||||||| | || |||||||| ||||||||||||||| | |
Db 1024 ATGGAGCTGAGGAGCCTGAGGTCTGACGACACGGCCGTGTATTACTGTGCGTTGGG---- 1079
Qy 301 GACTACAGGGGCTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCC 360
| | | ||||||||| || ||| |||||||||||||
Db 1080 -----------------GGCCTTTGTTTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC 1122
Qy 361 TCAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGAA 420
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1123 TCAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGAT 1182
Qy 421 ATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTC 480
||||| |||| ||||||||| | ||||| | | | || || || ||| || ||
Db 1183 GTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATC 1242
Qy 481 TCCTGCAGGGCCAGTCAGAGTGTT---------------ATCAACTACTTAGCCTGGTAC 525
||||||||| | ||||||||| || | || ||| || | ||||||
Db 1243 TCCTGCAGGTCTAGTCAGAGTCTTGCAAACAGTTATGGGAACACCTATTTGTCTTGGTAC 1302
Qy 526 CAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCTCT 585
| ||||| || || ||| |||| |||||| ||||||| |||||||| |||
Db 1303 CTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATGGGATTTCCAACAGATTTTCT 1362
Qy 586 GGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC 645
|| |||| | |||||||||||||||||| || || ||||| || || || | ||||||
Db 1363 GGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGC 1422
Qy 646 AGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTCGCAACTGGCCGCTC 705
|| | ||| |||| || ||| ||||||||||| || || | |||| |
Db 1423 AGAGTGGAGGCTGAGGACGTTGGGGTTTATTACTGCTTACAAGGTACACATCAGCCGTAC 1482
Qy 706 ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAACCACTACCCCAGCACCGAGGCCACCC 765
|| || ||| ||||||||| ||||||||||||||||||||||||||||||||||||||
Db 1483 ACGTTTGGCCAGGGGACCAAGCTGGAGATCAAAACCACTACCCCAGCACCGAGGCCACCC 1542
Qy 766 ACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCC 825
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1543 ACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCC 1602
Qy 826 GCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGG 885
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1603 GCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGG 1662
Qy 886 GCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT 945
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1663 GCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT 1722
Qy 946 AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCC 1005
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1723 AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCC 1782
Qy 1006 GGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGC 1065
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1783 GGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGC 1842
Qy 1066 TCCAAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTG 1125
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1843 TCCAAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTG 1902
Qy 1126 GAACACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTC 1185
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1903 GAACACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTC 1962
Qy 1186 CTGGACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTT 1245
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1963 CTGGACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTT 2022
Qy 1246 CTGCAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCA 1305
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2023 CTGCAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCA 2082
Qy 1306 AATCAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAGCGCGTGAAATTC 1365
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2083 AATCAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAGCGCGTGAAATTC 2142
Qy 1366 AGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTC 1425
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2143 AGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTC 2202
Qy 1426 AATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAA 1485
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2203 AATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAA 2262
Qy 1486 ATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAG 1545
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2263 ATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAG 2322
Qy 1546 GATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAA 1605
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2323 GATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAA 2382
Qy 1606 GGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTT 1665
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2383 GGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTT 2442
Qy 1666 CACATGCAGGCCCTGCCGCCTCGG 1689
||||||||||||||||||||||||
Db 2443 CACATGCAGGCCCTGCCGCCTCGG 2466
Alignment of SEQ ID NO: 13 of the ‘778 Application and instant SEQ ID NO: 4:
Query Match 51.2%; Score 1280.8; DB 1; Length 2466;
Best Local Similarity 85.7%;
Matches 1461; Conservative 0; Mismatches 207; Indels 36; Gaps 2;
Qy 1 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTC 60
||||| ||||||||| ||||||| | | ||| |||||||| || ||| ||
Db 784 CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTC 843
Qy 61 TCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCT 120
||||| || ||||| | |||||| | || || ||||||||||| || |||||
Db 844 TCCTGCAAGGCTTCTGGTTACACCTTTACCGACTTTGAAATGCACTGGGTGCGACAGGCC 903
Qy 121 CCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATTCTAT 180
|| || | ||||| |||||| ||| || ||| || || ||| |||
Db 904 CCTGGACAAGGGCTTGAGTGGATGGGAGATATTGATCCTGGAACTGGTGATACTGCCTAC 963
Qy 181 GCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT 240
| |||||| || ||||||| ||| ||||| |||| || ||| ||
Db 964 AATCTGAAGTTCAAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC 1023
Qy 241 CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGGAGAAGT 300
|| | ||| |||||||| | || |||||||| ||||||||||||||| | |
Db 1024 ATGGAGCTGAGGAGCCTGAGGTCTGACGACACGGCCGTGTATTACTGTGCGTTGGG---- 1079
Qy 301 GACTACAGGGGCTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCC 360
| | | ||||||||| || ||| |||||||||||||
Db 1080 -----------------GGCCTTTGTTTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC 1122
Qy 361 TCAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGAA 420
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1123 TCAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGAT 1182
Qy 421 ATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTC 480
||||| |||| ||||||||| | ||||| | | | || || || ||| || ||
Db 1183 GTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATC 1242
Qy 481 TCCTGCAGGGCCAGTCAGAGTGTT---------------ATCAACTACTTAGCCTGGTAC 525
||||||||| | ||||||||| || | || ||| || | ||||||
Db 1243 TCCTGCAGGTCTAGTCAGAGTCTTGCAAACAGTTATGGGAACACCTATTTGTCTTGGTAC 1302
Qy 526 CAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCTCT 585
| ||||| || || ||| |||| |||||| ||||||| |||||||| |||
Db 1303 CTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATGGGATTTCCAACAGATTTTCT 1362
Qy 586 GGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC 645
|| |||| | |||||||||||||||||| || || ||||| || || || | ||||||
Db 1363 GGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGC 1422
Qy 646 AGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTCGCAACTGGCCGCTC 705
|| | ||| |||| || ||| ||||||||||| || || | |||| |
Db 1423 AGAGTGGAGGCTGAGGACGTTGGGGTTTATTACTGCTTACAAGGTACACATCAGCCGTAC 1482
Qy 706 ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAACCACTACCCCAGCACCGAGGCCACCC 765
|| || ||| ||||||||| ||||||||||||||||||||||||||||||||||||||
Db 1483 ACGTTTGGCCAGGGGACCAAGCTGGAGATCAAAACCACTACCCCAGCACCGAGGCCACCC 1542
Qy 766 ACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCC 825
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1543 ACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCC 1602
Qy 826 GCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGG 885
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1603 GCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGG 1662
Qy 886 GCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT 945
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1663 GCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT 1722
Qy 946 AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCC 1005
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1723 AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCC 1782
Qy 1006 GGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGC 1065
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1783 GGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGC 1842
Qy 1066 TCCAAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTG 1125
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1843 TCCAAAAAAAGGATTAAGCCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTG 1902
Qy 1126 GAACACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTC 1185
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1903 GAACACCTTTGTAAGAAACCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTC 1962
Qy 1186 CTGGACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTT 1245
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1963 CTGGACTGCCAGATTCATAGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTT 2022
Qy 1246 CTGCAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCA 1305
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2023 CTGCAAGATACGTTTCCTCAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCA 2082
Qy 1306 AATCAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAGCGCGTGAAATTC 1365
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2083 AATCAAGAAGAAGCATATGTCACCATGTCCAGCTTCTACCAAAACCAGCGCGTGAAATTC 2142
Qy 1366 AGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTC 1425
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2143 AGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTC 2202
Qy 1426 AATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAA 1485
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2203 AATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAA 2262
Qy 1486 ATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAG 1545
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2263 ATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAG 2322
Qy 1546 GATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAA 1605
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2323 GATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAA 2382
Qy 1606 GGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTT 1665
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2383 GGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTT 2442
Qy 1666 CACATGCAGGCCCTGCCGCCTCGG 1689
||||||||||||||||||||||||
Db 2443 CACATGCAGGCCCTGCCGCCTCGG 2466
Alignment of SEQ ID NO: 14 of the ‘778 Application and instant SEQ ID NO: 4:
Query Match 75.2%; Score 2466; DB 1; Length 2466;
Best Local Similarity 100.0%;
Matches 2466; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTC 60
Qy 61 TCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCT 120
Qy 121 CCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATTCTAT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 CCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATTCTAT 180
Qy 181 GCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT 240
Qy 241 CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGGAGAAGT 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGGAGAAGT 300
Qy 301 GACTACAGGGGCTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GACTACAGGGGCTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCC 360
Qy 361 TCAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGAA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 TCAGGCAGTACTAGCGGTGGTGGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGAA 420
Qy 421 ATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 ATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTC 480
Qy 481 TCCTGCAGGGCCAGTCAGAGTGTTATCAACTACTTAGCCTGGTACCAACAGAAACCTGGC 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 TCCTGCAGGGCCAGTCAGAGTGTTATCAACTACTTAGCCTGGTACCAACAGAAACCTGGC 540
Qy 541 CAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCTCTGGCATCCCAGCCAGG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 CAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCTCTGGCATCCCAGCCAGG 600
Qy 601 TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAA 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAA 660
Qy 661 GATTTTGCAGTTTATTACTGTCAGCAGCGTCGCAACTGGCCGCTCACTTTCGGCGGAGGG 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 GATTTTGCAGTTTATTACTGTCAGCAGCGTCGCAACTGGCCGCTCACTTTCGGCGGAGGG 720
Qy 721 ACCAAGGTGGAGATCAAAGGAGGTGGTGGATCCGGAGGTGGTGGCTCCGGAGGTGGTGGA 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 ACCAAGGTGGAGATCAAAGGAGGTGGTGGATCCGGAGGTGGTGGCTCCGGAGGTGGTGGA 780
Qy 781 TCCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 TCCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG 840
Qy 841 GTCTCCTGCAAGGCTTCTGGTTACACCTTTACCGACTTTGAAATGCACTGGGTGCGACAG 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 GTCTCCTGCAAGGCTTCTGGTTACACCTTTACCGACTTTGAAATGCACTGGGTGCGACAG 900
Qy 901 GCCCCTGGACAAGGGCTTGAGTGGATGGGAGATATTGATCCTGGAACTGGTGATACTGCC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 GCCCCTGGACAAGGGCTTGAGTGGATGGGAGATATTGATCCTGGAACTGGTGATACTGCC 960
Qy 961 TACAATCTGAAGTTCAAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCC 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 TACAATCTGAAGTTCAAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCC 1020
Qy 1021 TACATGGAGCTGAGGAGCCTGAGGTCTGACGACACGGCCGTGTATTACTGTGCGTTGGGG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 TACATGGAGCTGAGGAGCCTGAGGTCTGACGACACGGCCGTGTATTACTGTGCGTTGGGG 1080
Qy 1081 GCCTTTGTTTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGCAGTACTAGCGGT 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 GCCTTTGTTTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGCAGTACTAGCGGT 1140
Qy 1141 GGTGGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGATGTTGTGATGACTCAGTCT 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 GGTGGCTCCGGGGGCGGTTCCGGTGGGGGCGGCAGCAGCGATGTTGTGATGACTCAGTCT 1200
Qy 1201 CCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAG 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 CCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAG 1260
Qy 1261 AGTCTTGCAAACAGTTATGGGAACACCTATTTGTCTTGGTACCTGCAGAAGCCAGGGCAG 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 AGTCTTGCAAACAGTTATGGGAACACCTATTTGTCTTGGTACCTGCAGAAGCCAGGGCAG 1320
Qy 1321 TCTCCACAGCTCCTGATCTATGGGATTTCCAACAGATTTTCTGGGGTCCCTGACAGGTTC 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1321 TCTCCACAGCTCCTGATCTATGGGATTTCCAACAGATTTTCTGGGGTCCCTGACAGGTTC 1380
Qy 1381 AGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGAC 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1381 AGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGAC 1440
Qy 1441 GTTGGGGTTTATTACTGCTTACAAGGTACACATCAGCCGTACACGTTTGGCCAGGGGACC 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1441 GTTGGGGTTTATTACTGCTTACAAGGTACACATCAGCCGTACACGTTTGGCCAGGGGACC 1500
Qy 1501 AAGCTGGAGATCAAAACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATC 1560
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1501 AAGCTGGAGATCAAAACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATC 1560
Qy 1561 GCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTG 1620
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1561 GCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTG 1620
Qy 1621 CATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACT 1680
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1621 CATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACT 1680
Qy 1681 TGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAGGAGTAAGAGGAGCAGG 1740
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1681 TGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAGGAGTAAGAGGAGCAGG 1740
Qy 1741 CTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCAT 1800
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1741 CTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCAT 1800
Qy 1801 TACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAAAAAAAGGATTAAG 1860
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1801 TACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAAAAAAAGGATTAAG 1860
Qy 1861 CCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAACACCTTTGTAAGAAA 1920
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1861 CCTATCGTATGGCCCAGTCTCCCCGATCACAAGAAGACTCTGGAACACCTTTGTAAGAAA 1920
Qy 1921 CCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTGGACTGCCAGATTCAT 1980
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1921 CCAAGAAAAAATTTAAATGTGAGTTTCAATCCTGAAAGTTTCCTGGACTGCCAGATTCAT 1980
Qy 1981 AGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTGCAAGATACGTTTCCT 2040
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1981 AGGGTGGATGACATTCAAGCTAGAGATGAAGTGGAAGGTTTTCTGCAAGATACGTTTCCT 2040
Qy 2041 CAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAATCAAGAAGAAGCATAT 2100
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2041 CAGCAACTAGAAGAATCTGAGAAGCAGAGGCTTCTGGGATCAAATCAAGAAGAAGCATAT 2100
Qy 2101 GTCACCATGTCCAGCTTCTACCAAAACCAGCGCGTGAAATTCAGCCGCAGCGCAGATGCT 2160
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2101 GTCACCATGTCCAGCTTCTACCAAAACCAGCGCGTGAAATTCAGCCGCAGCGCAGATGCT 2160
Qy 2161 CCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAG 2220
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2161 CCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAG 2220
Qy 2221 GAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGC 2280
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2221 GAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGC 2280
Qy 2281 AGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCC 2340
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2281 AGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCC 2340
Qy 2341 TATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTAC 2400
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2341 TATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTAC 2400
Qy 2401 CAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCG 2460
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2401 CAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCG 2460
Qy 2461 CCTCGG 2466
||||||
Db 2461 CCTCGG 2466
The claims in the ‘764 Application differ from the instant invention by not reciting only the CAR constructs of SEQ ID NOs: 5, 7, and 8 and their corresponding nucleic acids (SEQ ID NOs: 11, 13, and 14) or a fusion protein comprising only a truncated form of IL7R
α
, not full length IL7R
α
.
The teachings of Kong are outlined in the 102 rejection above. Kong also teaches that in order to induce a cytokine signal in an antigen-dependent manner during stimulation of cancer antigens, a cleaved (or truncated) cytoplasmic domain of interleukin-7 receptor-α (IL7Rα) in addition to the CD3ζ signaling domain and a 4-1BB costimulatory domain was added to a CAR gene so as to reduce the differentiation and exhaustion of CAR-T cells caused by CAR tonic signaling of CAR-T cells, thereby making it capable of exhibiting excellent in vivo persistence and anti-tumor effects (e.g. see [0005]).
Thus, it would be obvious to one of ordinary skill in the art modify the ‘764 Application to incorporate the teachings of Kong to specifically select the CAR constructs of the ‘764 Application that comprise a truncated body of IL7R
α
. This is because the inclusion of a cleaved (or truncated) cytoplasmic domain of IL7Rα in a CAR construct reduces the differentiation and exhaustion of CAR-T cells caused by CAR tonic signaling of CAR-T cells.
Given that the addition of a cleaved (or truncated) cytoplasmic domain of IL7Rα to the intracellular signaling domain is used to induce a cytokine signal in an antigen-dependent manner during stimulation of cancer antigens and can reduce the differentiation and exhaustion of CAR-T cells caused by CAR tonic signaling of CAR-T cells, thereby making it capable of exhibiting excellent in vivo persistence and anti-tumor effects; it would be obvious to a skilled artisan, with the goal of selecting the most efficient CAT constructs of the ‘764 Application, to specifically select SEQ ID NOs: 5, 7, and 8 and their corresponding nucleic acids (SEQ ID NOs: 11, 13, and 14) with a reasonable expectation of success.
It is noted that obtaining cDNA / nucleic acids from protein sequences has been routine and conventional in the art and used to make proteins of interest, including CARs of interest. For example, expression vectors can comprise polynucleotides sequences encoding amino acids, in turn CARs (e.g., CARs comprising a truncated body of IL7R
α
). Given that obtaining cDNA / nucleic acids from protein sequence sequences is routine and conventional, it would have been obvious to the ordinary artisan to obtaining cDNA to produce proteins of interest.
This applies to the instant case where it would be obvious to a skilled artisan to obtain the nucleic acid, fusion nucleic acid, expression vector of the instant invention from the CAR constructs of the ‘764 Application.
As such, the claims in the ‘764 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5-7, 10, and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-16 of U.S. Application No. 18/018,764 (the ‘764 Application) in view of Kong (WO 2020/050667, published 3/12/2020, claimed priority to 9/5/2018) as evidenced by Kong (US 20220387503) and Renaud-Gabardos et al. 2015 (World J Exp Med. 5(1): 11-20).
The instant claims are drawn to a truncated body of IL7Rα, wherein the amino acid sequence of the truncated body of IL7Rα is a sequence shown in SEQ ID NO. 1; an expression vector; a cell; and a pharmaceutical composition.
The claims in the ‘764 Application are drawn to a fusion protein that has an amino acid sequence shown in any of SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7 or SEQ ID NO. 8; and a fusion nucleic acid that has a nucleotide sequence shown in any of SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, or SEQ ID NO. 14; and a fusion protein comprising IL7Rα or a truncated form thereof.
It is noted that SEQ ID NOs: 5, 7, and 8 of the ‘764 Application are CAR constructs that comprise a truncated body of IL7R
α
that is identical to instant SEQ ID NO: 1. See sequence alignments above. SEQ ID NOs: 3, 4, and 6 of the ‘764 Application do not comprise a truncated body of IL7R
α
. It is further noted that SEQ ID NOs: 9-14 of the ‘764 Application are nucleic acid sequences encoding SEQ ID NOs: 3-8, respectively.
It is also noted that SEQ ID NOs: 11, 13, and 14 of the ‘778 Application comprise or are identical to either all or part of instant SEQ ID NOs: 2 and 4. See sequence alignments above.
The claims in the ‘764 Application differ from the instant invention by not reciting only the CAR constructs of SEQ ID NOs: 5, 7, and 8 and their corresponding nucleic acids (SEQ ID NOs: 11, 13, and 14); a fusion protein comprising only a truncated form of IL7Rα, not full length IL7Rα; or that an IRES element encoding sequence is inserted between the first nucleic acid fragment encoding an antigen binding molecule and the second nucleic acid fragment encoding an intracellular signaling molecule.
The teachings of Kong are outlined in the 102 and NSDP rejections above.
Renaud-Gabardos et al. teach that internal ribosome entry sites (IRESs), RNA elements naturally present in the 5’ untranslated regions of a few mRNAs, constitute a powerful tool to co-express several genes of interest (e.g. see Abstract). IRESs are translational enhancers allowing the translational machinery to start protein synthesis by internal initiation. This feature allows for the design of multi-cistronic vectors expressing several genes from a single mRNA (e.g. see Abstract). IRESs have been used to generate transgene co-expression under the control of a single promoter (e.g. see page 12, right column, third paragraph).
Thus, it would be obvious to one of ordinary skill in the art modify the ‘764 Application to incorporate the teachings of Kong to specifically select the CAR constructs of the ‘764 Application that comprise a truncated body of IL7R
α
and to specifically select the CAR constructs of the ‘764 Application that comprise a truncated body of IL7Rα and to include that an IRES element encoding sequence is inserted between the first nucleic acid fragment encoding an antigen binding molecule and the second nucleic acid fragment encoding an intracellular signaling molecule. This is because the inclusion of a cleaved (or truncated) cytoplasmic domain of IL7Rα in a CAR construct reduces the differentiation and exhaustion of CAR-T cells caused by CAR tonic signaling of CAR-T cells and IRESs constitute a powerful tool to co-express several genes of interest.
Given that the addition of a cleaved (or truncated) cytoplasmic domain of IL7Rα to the intracellular signaling domain is used to induce a cytokine signal in an antigen-dependent manner during stimulation of cancer antigens and can reduce the differentiation and exhaustion of CAR-T cells caused by CAR tonic signaling of CAR-T cells, thereby making it capable of exhibiting excellent in vivo persistence and anti-tumor effects; it would be obvious to a skilled artisan, with the goal of selecting the most efficient CAT constructs of the ‘764 Application, to specifically select SEQ ID NOs: 5, 7, and 8 and their corresponding nucleic acids (SEQ ID NOs: 11, 13, and 14) with a reasonable expectation of success.
It is noted that obtaining cDNA / nucleic acids from protein sequences has been routine and conventional in the art and used to make proteins of interest, including CARs of interest. For example, expression vectors can comprise polynucleotides sequences encoding amino acids, in turn CARs (e.g., CARs comprising a truncated body of IL7R
α
). Given that obtaining cDNA / nucleic acids from protein sequence sequences is routine and conventional, it would have been obvious to the ordinary artisan to obtaining cDNA to produce proteins of interest.
This applies to the instant case where it would be obvious to a skilled artisan to obtain the nucleic acid, fusion nucleic acid, expression vector of the instant invention from the CAR constructs of the ‘764 Application.
Furthermore, given that IRESs are translational enhancers that allow for the design of multi-cistronic vectors expressing several genes from a single mRNA and that they have been used to generate transgene co-expression under the control of a single promoter; it would have been obvious to a skilled artisan, with the goal of translating the antigen binding molecule and intracellular signaling molecule of the CAR separately but from a single expression vector under the control a single promoter, to include an IRES element encoding sequence between the nucleic acid fragment encoding the antigen binding molecule and the nucleic acid fragment encoding the intracellular signaling molecule in an expression vector encoding ‘764 Application’s CAR constructs of SEQ ID NOs: 5, 7, and 8.
As such, the claims in the ‘764 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Grace H. Lunde whose telephone number is (703)756-1851. The examiner can normally be reached Monday - Thursday 5:00 a.m. - 3:00 p.m. (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/CHUN W DAHLE/Primary Examiner, Art Unit 1641