Detailed Action
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-23 were originally filed 13 June 2023. The preliminary amendment filed the same day has been entered. Claims 24, 28, 30, 31, and 36 are currently pending and under consideration.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Withdrawn Claim Objections
In view of Applicant’s amendments to claims 24 the objection to extra spacing in line 3, and “CD28 costimulatory signal domain”, the claim objections regarding these matters are hereby withdrawn.
In view of Applicant’s amendments to claim 31 and canceling claim 32 the claim objections are hereby withdrawn.
Claim Objections
It is noted the following claim objections have been amended to reflect objections to Applicant’s amendments.
Claims 24 and 31 are objected to because of the following informalities:
Claim 24 has an extra space between “antigen binding” in lines 6 and 10, “signal stimulation” in line 8 (see black underline below).
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Claim 31 is drawn to more than one (a), (b), (c), (d), (e), and (f). The claim should be rewritten to make clear that each part (a) belongs to separate structures. For example, “wherein the chimeric antigen receptor comprises one of the following:
I (a), (b), (c), (d), (e), and (f); or
II (a), (b), (c), (d), (e), and (f).”
Appropriate correction is required.
Withdrawn Claim Rejections
In view of Applicant’s amendment to claim 36 the 35 USC 112(b) rejection over said claim is hereby withdrawn.
In view of Applicant canceling claims 27, 32, and 38 the 35 USC 112(b) rejections (i.e., claims 27 and 32) and applicable 35 USC 112(d) rejections (i.e., claims 27 and 38) over said claims are hereby withdrawn.
In view of Applicant amending claims 30 and 36 the 35 USC 112(d) rejection over said claims is hereby withdrawn.
Maintained Claim Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 24, 28, 30, 31, and 36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The scope of the CAR structure in claim 24 is unclear. The language of the claim is draw to various domains/regions of the CAR; however, it is unclear what structures are associated with particular regions.
Claim 24 is drawn to a GPC3 antigen binding domain comprising a GC33 scFv comprising Seq ID Nos: 9 and 11. The scope of the GPC3 antigen binding domain is unclear. The state of the art teaches GC33 is a known GPC3 antigen binding domain comprising a VH-linker-VL with the following sequence:
QVQLQQSGAELVRPGASVKLSCKASGYTFTDYEMHWVKQTPVHGLKWIGALDPKTGDTAYSQKFKGKATLTADKSSSTAYMELRSLTSEDSAVYYCTRFYSYTYWGQGTLVTVSAGGGGSGGGGSGGGGSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQNTHVPPTFGSGTKLEIK (see Heczey, as cited on the PTO-892 mailed 02/06/2025, Seq ID NO: 24, pg. 4, para spanning cols. 1-2). However, while instant Seq ID No: 9 is identical to the GC33 scFv disclosed in Heczey instant Seq ID No: 11 is not identical.
Heczey Seq ID No: 24 QVQLQQSGAELVRPGASVKLSCKASGYTFTDYEMHWVKQTPVHGLKWIGALDPKTGDT
Instant Seq ID No: 9 QVQLQQSGAELVRPGASVKLSCKASGYTFTDYEMHWVKQTPVHGLKWIGALDPKTGDT
Heczey Seq ID No: 24 AYSQKFKGKATLTADKSSSTAYMELRSLTSEDSAVYYCTRFYSYTYWGQGTLVTVSA
Instant Seq ID No: 9 AYSQKFKGKATLTADKSSSTAYMELRSLTSEDSAVYYCTRFYSYTYWGQGTLVTVSA
Heczey Seq ID No: 24 GGGGSGGGGSGGGGSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYL
Instant Seq ID No: 11 DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYL
Heczey Seq ID No: 24 QKPG---QSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQNTHVPP
Instant Seq ID No: 11 QKPGGINSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQNTHVPP
Heczey Seq ID No: 24 TFGSGTKLEIK
Instant Seq ID No: 11 TFGSGTKLE
*bold text indicated deviation from art recognized GC33 sequence
Thus, it is unclear if the GPC3 antigen binding domain is limited to the art recognized sequences of GC33 as set forth in Heczey or alternatively is the GPC3 antigen binding domain limited to instant Seq ID Nos: 9 and 11.
In addition, claim 24 is drawn to ICD1 and ICD3 (see lines 4 and 8). The specification discloses “we design three intracellular signal domains, ICD1, ICD2, and ICD3” (see specification pg. 4 para [0016]). It is therefore unclear if ICD is an acronym for “intracellular signal domain” as suggested by the specification, or alternatively, arbitrary lab designations for particular sequences.
Claim 30 is drawn to wherein “the GPC3 antigen binding domain is GC33 scFv with the amino acid sequence Seq ID NO: 13”. The scope of the GPC3 antigen binding domain is unclear. For example, is the GPC3 antigen binding domain limited to a GC33 scFv comprising the amino acid sequence set forth in Seq ID No: 13, or alternatively, is the GPC3 antigen binding drawn to comprising both the art recognized GC33 scFv (see above) and Seq ID No: 13.
Claim 31 is drawn to a CAR comprising (in order) Seq ID Nos: 21, 19, 23 and 35. A CAR generally comprises an extracellular domain comprising an antigen binding domain and a hinge region followed by a transmembrane domain and various intracellular domains. Claim 32 is drawn to a CAR with the following structure: antigen binding domain-hinge-transmembrane domain- CD28 signal domain-portion of hinge domain-ICD3-CD3 conduction domain. However, instant Seq ID No: 23 comprises both a CD28 signal domain as well as the last 13 amino acids of the CD8 hinge region.
Seq ID NO: 21 CD8 hinge: TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD
Seq ID NO: 23 CD28 domain: RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSGAVHTRGLDFACD
Thus, the scope of the CAR is unclear. For example, does the CAR comprise the domains as recited in lines 2 and 3 or alternatively does the CAR comprise an additional portion of the CD8 hinge region as set forth in Seq ID No: 23.
Applicant's arguments filed 28 May 2026 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Regarding claim 24, Applicant argues amending the claim to recite the intracellular signal stimulation domain “comprises” makes clear the ordinary artisan the intracellular signal stimulation domain must contain all three components (i.e., CD28 costimulatory signal domain, ICD1 or ICD3, and CD3ζ (see Remarks pg. 6, 2nd para).
However, the scope of the intracellular signal stimulation domain remains unclear. For example, is the intracellular signal stimulation domain drawn to comprising a CD28 costimulatory signal domain, ICD1, and a CD3ζ domain, alternatively, a CD28 costimulatory signal domain, ICD1, and a CD3ζ domain, and the GPC3 antigen binding domain given it is listed within the same wherein clause and separated by a comma, which suggests the binding domain is also part of the list.
In addition, Applicant argues that claim 24 “explicitly defines GPC3 antigen binding domain as a GC33 scFv containing the amino acid sequences set forth in Seq ID Nos: 9 and 11”, which Applicant states is supported in the specification and leaves no ambiguity as to what the claimed GC33 scFv structure (see Remarks pg. 6, 3rd para).
First, the claim recites the GC33 scFv “containing amino acid sequences set forth in Seq ID No: 9 and 11”. This language encompasses sequence fragments of Seq ID Nos: 9 and 11. Given GC33 scFv has art recognized structure the ordinary artisan would not be clear if the claimed structure is limited to the art recognized portions of the GC33 scFv found in Seq ID Nos: 9 and 11 or if the GPC3 antigen binding domain comprises the entirety of Seq ID Nos: 9 and 11. Second, while the specification does disclose the GC33 scFv contains amino acids sequences Seq ID Nos: 9 and 11 (see specification pg. 5 para [0024]), the specification also discloses the GC33 scFv has the amino acid sequence Seq ID No: 13 (see specification pg. 5 para [0025]). Therefore, the GC33 scFv in the specification is drawn to a genus of structures and is not clearly defined.
Applicant argues ICD is clearly an abbreviation for intracellular signal domain and points to the specification,
“we design three intracellular signal domains, ICD1, ICD2 and ICD3” (see specification pg. 4, para [0016]; see Remarks pg. 6, 4th para).
However, this portion of the specification discloses that ICD1, ICD2, and ICD3 are species of a genus of intracellular signal domains. Abbreviations are conventionally established by reciting the abbreviation between “()” immediately after the term (e.g., intracellular signal domain (ICD)).
Regarding claim 30, Applicant argues amending claim 30 to depend from claim 24 makes the claim clear and definite. However, the claim recites “the GPC3 antigen binding domain is GC33 scFv with the amino acid sequence Seq ID No: 13”. It remains unclear if the GC33 scFv is the same GC33 scFv recited in claim 24. In addition the claim is recites the word “with”, given GC33 has art recognized structure it is unclear if the GPC3 antigen binding domain encompasses the art recognized structure comprising the recited sequence, alternatively, the art recognized structure with a second structure comprising Seq ID NO: 13.
Applicant has amended claim 31 to recite the limitations of the previous claim 32. The scope of the CAR remains unclear. On the one hand, the claim 31 recites the sequential order of domains in the CAR, on the other hand the claim also recites particular sequences for each sequential domain. However, claim 31(d) recites, “a CD28 costimulatory signal domain comprising the amino acid sequence set forth in Seq ID NO: 23”. The recited sequence comprises more than ten additional amino acids identical to a portion of the CD8 hinge. Therefore, it is unclear if the claim is drawn to the portions of Seq ID No: 23 that is the CD28 costimulatory domain or alternatively the entirety of Seq ID No: 23. In the case of the later it is unclear how the claim can comprise a CD28 costimulatory domain which is not a CD28 costimulatory domain (i.e., comprises additional non-CD28 costimulatory domain amino acids).
Claim 31 is dependent from claim 24 wherein the GPC3 antigen binding domain is a GC33 scFv comprising either portions or the entirety of Seq ID Nos: 9 and 11. Claim 31 is drawn to “a GC33 scFv”. IT is unclear if the claim is drawn to an additional GC33 scFv, alternatively, the art recognized GC33 scFv sequence, or alternatively, the GC33 scFv recited in claim 24.
Allowable Subject Matter
The following claims 24, 30, 31, and 36 are drafted by the examiner and considered to distinguish patentably over the art of record in this application, are presented to applicant for consideration:
24. A polynucleotide encoding a chimeric antigen receptor and an IL-15-IL- 15Ra fusion protein, wherein the chimeric antigen receptor comprises a GPC3 antigen binding domain and an intracellular signal domain, wherein the GPC3 antigen binding domain comprises SEQ ID NO: 9 and 11, and wherein the intracellular signal domain comprises:
(a) a CD28 costimulatory signal domain,
(b) intracytoplasmic signal domain (ICD)1 comprising SEQ ID No: 29 or ICD3 comprising SEQ ID NO: 33, and
(c) a CD3ζ signal conduction domain.
30. The polynucleotide according to claim 24, wherein the GPC3 antigen binding domain comprises SEQ ID NO: 13.
31. cancelled.
36. An expression vector comprising the polynucleotide of claim 24, wherein the ICD1 or ICD3 are encoded by a nucleic acid sequence comprising Seq ID No: 30 or 34, respectively.
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HILARY ANN PETRASH whose telephone number is (703)756-4630. The examiner can normally be reached Monday-Friday 8:30-4:30 EST.
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/H.A.P./ Examiner, Art Unit 1644
/AMY E JUEDES/ Primary Examiner, Art Unit 1644
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