DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 21-37 are newly added. Claims 1-37 are pending and are examined on the merits.
OBJECTIONS WITHDRAWN
Objections to the specification over a deficient incorporation by reference paragraph and lack of antecedent basis for the “kit” of claim 15 are withdrawn in view of applicant’s amendments to the specification.
REJECTIONS WITHDRAWN
Rejections of Claims 1-20 made under 35 U.S.C. 102(a)(1) as anticipated by Lim et al. 2018 are withdrawn in view of applicant’s amendments.
REJECTIONS MAINTAINED
Claim Rejections - 35 USC § 112
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.
Claim 5 remains 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.
A broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance Claim 5 recites the broad limitation of a “tamoxifen or a metabolite thereof” followed by a narrower set of “optional” compounds (e.g. h-hydroxytamoxifen, N-desmethyltamoxifen, etc.). The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Response to Arguments
Applicant's arguments filed 12/11/2025 have been fully considered but they are not persuasive.
Claim 5 was previously rejected for reciting “optional” limitations that are narrower expressions of a broader limitation required by the claim. In applicant’s remarks, “Applicants submit that claims 1-8, 14-18 and 20 have been amended to remove the term “optionally”” (Remarks Pg. 29)
However, as pointed out above, Claim 5 continues to recite optional limitations following this same pattern (broad and narrow in the same claim) and the rejection is therefore maintained.
NEW OBJECTIONS
Claim Objections
Claim 22 is objected to because of the following informalities:
The phrase “wherein each secretion signal peptide comprises a non-native secretion signal peptide that is non-native to the corresponding effector molecule” is repeated twice in immediate succession.
Appropriate correction is required.
NEW AND UPDATED REJECTIONS AS NECESSITATED BY CLAIM AMENDMENTS
Claim Rejections - 35 USC § 112
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 2, 21-22, 24, and 28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 is indefinite for reciting a linker polynucleotide sequence localized between the first and second expression cassettes, wherein the linker polynucleotide encodes a 2A ribosome skipping tag that is “operably associated with the translation of the ACP and each effector molecule as separate polypeptides”. As required by Claim 1, from which Claim 2 depends, the first and second expression cassettes each comprise a discrete promoter operably linked to the expression of 1) the “ACP” and 2) one or more effector molecules. Because the gene products of first and second expression cassettes are under control of separate promoters, they are necessarily produced as separate polypeptides from discrete transcripts. It is therefore unclear how a 2A sequence situated between the first and second expression cassettes could be operably associated with the translation of the ACP and effector molecule as separate polypeptides when said ACP and effector molecule are expressed on two separate transcripts and the 2A sequence is not present on either one.
For the purposes of examination, the “linker polynucleotide” of Claim 2 is interpreted to encompass the linker polynucleotide of 1(b), which serves to facilitate separate expression of each of the one or more effector molecules of the second expression cassette.
Claim 21 recites the limitation “the corresponding secretion signal peptide” in the third wherein clause, which lacks antecedent basis. Claim 1, from which Claim 21 depends does not recite a “secretion signal peptide”. Although Claim 21 recites “wherein the second expression cassette...further comprises a polynucleotide sequence encoding a secretion signal peptide for each X” in the second wherein clause, the three wherein clauses are recited in the alternative (“and/or”), and therefore do not require or depend on one another. Thus, is it unclear to what “the corresponding secretion signal peptide” recited in the third wherein clause is referring.
Similarly, Claim 22 recites “the non-native secretion signal peptide” in the final wherein clause, which is expressed as an independent alternative limitation (“and/or”). Accordingly, phrase “the non-native secretion signal peptide” as recited lacks antecedent basis because the second wherein clause that establishes the limitation of a “non-native secretion signal peptide” is not necessarily a required feature of the claim.
Claim 24 depends from Claim 3 and recites “the promoter”, however, Claim 3 depends from Claim 1, which requires several promoters (e.g. of the first, second, and additional expression cassette), and it unclear to which “promoter” in particular the claim is drawn.
Claim 28 specifies that the antigen binding domain of the antigen recognizing receptor comprises an scFV, however the Claim further recites that the antigen recognizing receptor is a chimeric antigen receptor (CAR) or a T cell receptor (TCR). However, the antigen binding domain of a TCR is made up of paired α/β chain variable domains, as opposed to a VH and VL of an scFV as required by the claim. It is therefore unclear what a TCR having a binding domain comprising an scFv is meant to encompass.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6-7 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 6 and 7 recites “the additional expression cassette if present” (emphasis added). Claims 6-7 depend from Claims 4 and 1, which require the “additional expression cassette”. Accordingly, because Claims 6 and 7 read on species of the claimed invention wherein the additional expression cassette is not present, the claim fails to include all of the limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Improper Markush
Claims 30, 33, and 37 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush groupings recited in Claims 30, 33, and 37 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Claim 30 is drawn to the engineered expression system wherein the CAR comprises an intracellular signaling domain or a transmembrane domain. Because intracellular signaling domains and transmembrane domains are structurally distinct, occupy mutually exclusive cellular compartments, and perform vastly different functions, they would not reasonably be considered alternatives sharing a single structural similarity or common use.
Claims 33 and 37 are drawn to means of expressing the engineered expression system (e.g. “recombinantly expressed”) or wherein the cell is autologous or allogeneic. Because the source/origin of a cell and the mode of expression of a transgene read on entirely different structures and functions, they would not reasonably be considered alternatives sharing a single structural similarity or common use.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 29 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Scope of the claimed genus
Claim 29 is drawn to a CAR comprising a GPC3 binding domain wherein the GPC3 binding domain comprises a VH and VL defined by partial sequence identity (e.g. 90%, 91%, etc.) to the recited SEQ ID NOs, whereby there is no limit to where this sequence variability may occur. 10% variability in the VL of SEQ ID NO: 128, for example, would allow for substitutions, deletions, and insertions of up to ~13 residues – of any amino acid at any position, including the critical CDRs. Accordingly, the claim is drawn to countless potential GPC3 binders.
State of the relevant art
GPC3 antibodies and CAR T cells comprising GPC3 binding domains were known in the art. For example, Ho et al. 2019 (WO 2019/094482 A1; PTO-892) teaches the YP7/hYP7 anti-GPC3 binders of the instant disclosure and CARs comprising scFvs thereof (Abstract; Pg. 30-32). However, Ho does not teach any variability within the CDR sequences of the YP7/hYP7 binders.
As was well-known in the antibody art at the time of filing, the formation of an intact antigen-binding site in an antibody typically requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope (reviewed in Sela-Culang et al. Frontiers in immunology 4 (2013): 302.; PTO-892).
Further the skilled artisan has long recognized that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function, as evidenced by Rudikoff 1982 (PNAS 79.6 (1982): 1979-1983.; PTO-892). Rudikoff teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract). Although more recent advances in computational modelling of CDRs have led to improvements in rational mutagenesis of antibodies, the overall effects of any given mutation on antibody function remain unpredictable.
For example, Chiu et al. 2019 (Antibodies, 8(4), 55.; PTO-892) teaches that although modeling has proven accurate for framework region sequences, CDR modeling requires further development and improvement (Pg. 6, ¶2). In particular, prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (Pg. 6, ¶2). Chiu further states “despite the obvious development in algorithms and computer power, the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate” (Pg. 11, ¶ 2). Accordingly, the skilled artisan would have recognized that it was highly unpredictable that any of the instantly claimed CDRs could be modified without altering or abolishing GPC3 binding.
Description of representative species in the specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification discloses the VH, VL, and CDR sequences of the YP7/hYP7 antibodies already known in the art (SEQ ID NOs: 119-124). However, given each of the disclosed binders comprises the same CDRs, and no additional species comprising any modification thereof are disclosed, the two disclosed species would not reasonably be considered representative of the claimed genus.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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 claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed GPC3 binding activity.
The instant disclosure provides examples in which a single disclosed species of GPC3 binder is incorporated into a CAR (SEQ ID NO: 138). However, no structure/function relationship between the CDRs or VH/VL sequences of the anti-GPC3 binding domain is established. Accordingly, one of ordinary skill in the art would be unable to envisage GPC3 binding domains commensurate in scope with the claims.
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5 and 7-20 remain rejected and Claims 21-28 and 30-37 are newly rejected under 35 U.S.C. 102(a)(2) as being anticipated by Khalil et al. 2020 (WO 2020/232366 A2; Priority to 05/16/2019; IDS dated 03/31/2025).
Khalil teaches an engineered expression system comprising a first and second expression cassette comprising promoter sequences that drive separate expression of an inducible synthetic transcription factor (synTF; i.e. an “activation-conditional control polypeptide”; Fig. 10) and a gene of interest (including cytokines; e.g. ¶00644), respectively.
Khalil teaches the synTF (i.e. “ACP”) comprises a DNA-binding domain, a transcriptional effector domain, and a hormone binding domain of estrogen receptor (ERT2) wherein the ERT2 domain undergoes nuclear localization upon binding a tamoxifen molecule such as 4OHT (Abstract; ¶00644; Fig. 4, 10, 14A; Khalil claims 29-34).
Regarding instant Claims 1 and 4, Khalil teaches that can further comprise an additional expression cassette encoding a chimeric antigen receptor (¶00664; Fig. 14A, copied below), and that the first, second, third etc. polypeptides of the expression system can each be provided in a single vector (i.e. “encoded by the same polynucleotide”) (¶00398).
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Regarding instant Claims 7-9 and 19-20, Khalil teaches vectors, cells (including T cells, NK cells, etc.), and pharmaceutical compositions comprising the disclosed engineered expression system (Pg. 177-178, items 55-62).
Further, regarding Claim 7 and Claim 32-33, Khalil teaches that the first and second expression cassettes can be on the same vector oriented in opposite directions (¶00474) or on separate vectors (¶0023).
Regarding instant Claims 8, 33, and 37, Khalil teaches the cells can be allogeneic or autologous (¶00515).
Regarding instant Claim 2 and 23, Khalil teaches that multiple effector molecules can be linked by a 2A ribosome skipping sequence such as P2A (§ “Self Cleaving Peptide”, ¶00391-00398; Table 1, “pMN-268”; ¶00473).
Regarding instant Claims 10-14, 16-18, and 34-36, Khalil teaches a method of treating cancer, such as liver cancer, lung cancer, etc. (¶00563), comprising administering a population of cells comprising the engineered expression system and a regulator protein inducer such as 4-hydroxytamoxifen (4-OHT) (§ Treatment Methods; ¶00551; ¶00511; Khalil claims 63-69) wherein the administered cells are immune cells (treatment of cancer with an immune cell inherently encompasses the limitations “providing antitumor immunity” and “stimulating a cell-mediated immune response”)(Khalil claims 66-67). Further, regarding instant Claim 13, Khalil teaches that the efficacy of the method of treating can be determined by tumor size (¶00527).
Regarding instant Claim 15, absent a specific definition in the specification, a “kit” as claimed is interpreted to be drawn to a set of articles or equipment needed for a specific purpose. Accordingly, Khalil teaches pharmaceutical compositions for use in treating cancer comprising cells containing the engineered expression system described above along with pharmaceutically acceptable carriers or diluents, provided alongside a regulator protein inducer (e.g. 4-OHT) as a ready-to-injection solution or as dry product for suspension with a pharmaceutically acceptable diluent (¶00529-00531) – thereby satisfying the broadest reasonable interpretation of a “kit”.
Regarding instant Claims 24-26, Khalil teaches that the promoter for the effector molecule can be, for example, miniCMV, miniTK, etc. (Khalil claim 57), the binding domain comprises zinc finger binding sites (¶0120), and the synTF is under control of a constitutive promoter such as CMV (Khalil claim 58).
Regarding instant Claim 27, Khalil teaches the effector molecule can be a cytokine, such as IL-4 (e.g. Fig. 14A).
Regarding instant Claim 28, Khalil teaches that the CAR comprises an scFv having the structure VL-Linker-VH (partial annotation of Khalil SEQ ID NO: 373 below):
VL-Linker-VH
21...DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVS...262
Regarding instant Claim 30, Khalil teaches that the CAR comprises a CD28 transmembrane domain and a 41BB intracellular signaling domain as evidenced by UniProt ID P10747 (CD28_Human; PTO-892) and UniProt ID Q07011 (TNR9_Human; PTO-892), respectively (partial alignments annotated below):
Khalil SEQ 373 322...FWVLVVVGGVLACYSLLVTVAFIIFWV...347
|||||||||||||||||||||||||||
CD28 TM 153...FWVLVVVGGVLACYSLLVTVAFIIFWV...179
Khalil SEQ 373 390...KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL...431
||||||||||||||||||||||||||||||||||||||||||
TNR9 (4-1BB) 214...KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL...255
Regarding instant Claim 31, the synTF of Khalil (i.e. “ACP”) can be a transcriptional activator or repressor (e.g. Fig. 10A-B; Fig. 11).
Response to Arguments
Applicant's arguments filed 12/11/2025 have been fully considered but they are not persuasive.
Applicant has amended the claims to require a first expression cassette encoding an ACP having an ERT2 domain capable of undergoing nuclear localization upon binding a tamoxifen molecule (e.g. 4-OHT), a second expression cassette responsive to the ACP encoding a cytokine, and an “additional expression cassette” encoding an antigen-recognizing receptor. Applicant argues that the amendments differentiate the claimed invention from that of Khalil.
However, as acknowledged by Applicant: “Khalil describes the inducible synthetic transcriptional activation of a chimeric antigen receptor (in a dual- drug regulated context) in primary human cells, where administration of 4-OHT led to expression and secretion of IL4 cytokine from a ZF-responsive promoter in CD4+ primary human T cells. This system was used in conjunction with grazoprevir regulated activation of a fluorescently-tagged chimeric antigen receptor (CD19-CAR) protein from an orthogonal ZF-responsive promoter.” (Applicant Remarks, Pg. 6, last ¶).
Thus, by Applicant’s own characterization of the disclosure of Khalil, Khalil teaches 1) an ACP responsive to 4-OHT which, 2) regulates the expression of a cytokine, in combination with 3) an additional expression cassette encoding an antigen-recognizing receptor.
To the extent that Applicant argues that Khalil “relies on a dual-drug related system to induce the expression of a cytokine and of a CD19-CAR”, Examiner notes that the claims do not require that the additional expression cassette encoding the antigen-recognizing receptor be responsive to the same – or indeed any – “activation-control peptide”. Moreover, the example illustrated in Fig. 14A of Khalil is but one of many control systems taught and envisaged by the disclosure, and Khalil teaches that any number of genes of interest, including a cytokine and CAR, can be regulated by any combination of the control systems taught therein (e.g. ERT2/4-OHT, NS3/grazoprevir, etc.) (¶00494-00495; Fig. 10).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Khalil et al. 2020 (WO 2020/232366 A2; Priority to 05/16/2019; IDS dated 03/31/2025), herein Khalil, as applied to claims 1 and 4 above, and further in view of Hasegawa et al. 2002 (FEBS letters, 520(1-3), 47-52.), herein Hasegawa.
The teachings of Khalil are summarized above.
Regarding instant Claim 6, Khalil does not teach that the expression system further comprises an insulator between the first and second expression cassette. This deficiency is cured by Hasegawa
Hasegawa teaches that the expression of two transgene is often subject to mutual interference by each of the two expression cassettes when they are driven by different transcriptional regulatory elements (Abstract).
Hasegawa teaches that placing insulator elements between the expression cassettes prevents transcriptional interference and leakage between the two transgenes (Fig. 1-4).
It would have been obvious to one of ordinary skill in the art to modify the expression system of Khalil to further include an insulator element between the first and second expression cassette. The skilled artisan would have been motivated by the teachings of Hasegawa that multiple expression cassettes on the same vector often interfere with one another. There would have been a reasonable expectation of success because Hasegawa teaches that insulator elements prevent mutual inhibition and/or leaky expression in a double transgene vector.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Khalil et al. 2020 (WO 2020/232366 A2; Priority to 05/16/2019; IDS dated 03/31/2025), herein Khalil, as applied to claims 1 and 28 above, and further in view of Ho et al. 2019 (WO 2019/094482 A1; PTO-892), herein “Ho”.
The teachings of Khalil are summarized above
Regarding instant Claim 29, Khalil does not teach that the CAR targets GPC3 nor that the CAR comprises the instantly claimed sequences. This deficiency is cured by Ho.
Ho teaches that GPC3 is highly expressed in primary hepatocellular carcinoma (HCC) (Pg. 55, lines 1-18), and that the YP7 antibody shows strong binding to HCC cell lines.
Ho teaches GPC3-targeted CAR comprising a humanized YP7 scFv (hYP7), a CD8 transmembrane domain, and a 4-1BB/CD3zeta intracellular signaling domain (Pg. 46, Example 1; Fig. 10B).
Ho teaches that CAR T cells comprising the GPC3 CAR effectively induced tumor regression in an HCC mouse model with a 100% survival rate at the highest dose level (Pg. 59, lines 12-26; Fig. 14D).
Ho teaches the hYP7 binding domain comprises a VH and VL identical to instantly claimed SEQ ID NOs and 128, respectively (see alignment with Ho SEQ ID NOs: 26 and 28):
hYP7 VH (Instant SEQ ID NO: 126; Ho SEQ ID NO: 26)
SEQ126 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFNKNAMNWVRQAPGKGLEWVGRIRNKTNNYAT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ho26 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFNKNAMNWVRQAPGKGLEWVGRIRNKTNNYAT 60
SEQ126 61 YYADSVKARFTISRDDSKNSLYLQMNSLKTEDTAVYYCVAGNSFAYWGQGTLVTVSA 117
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ho26 61 YYADSVKARFTISRDDSKNSLYLQMNSLKTEDTAVYYCVAGNSFAYWGQGTLVTVSA 117
hYP7 VL (Instant SEQ ID NO: 128; Ho SEQ ID NO: 28)
SEQ128 1 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASSR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ho28 1 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASSR 60
SEQ128 61 ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYNYPLTFGQGTKLEIK 113
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Ho28 61 ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYNYPLTFGQGTKLEIK 113
It would have been obvious to one of ordinary skill in the art to substitute the CD19 CAR of Khalil with the hYP7 GPC3 CAR of Ho. The skilled artisan would have been motivated by the suggestion of Khalil that the expression system could be used to treat cancers such as liver cancer, and the teachings of Ho that GPC3 is a promising target for HCC. There would have been a reasonable expectation of success because Ho teaches that hYP7 CARs induced HCC tumor regression in an HCC mouse model.
Conclusion
No claim is 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 BRYAN WILLIAM HECK whose telephone number is (703)756-4701. The examiner can normally be reached Mon-Fri 8:00am - 5:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRYAN WILLIAM HECK/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643