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 .
Applicant's amendment and remarks, filed 9/14/26, are acknowledged.
Claims 31-32, 37 and 44 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claims 1-3, 5-6, 10-16, 19-22, 24-26, 29, and 40 are being acted upon.
In view of Applicant’s claim amendments and terminal disclaimer, only the following rejections remain. The rejections have been modified to the extent necessary to address Applicant’s claim amendments.
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 14-15 and 21-22 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 14 recites the limitation "the extracellular antigen-binding domain”" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 15 is indefinite in the recitation of a CD28 signaling domain; wherein the CD28 signaling domain comprises a transmembrane domain. Are the claims meant to be interpreted as a CD28 signaling domain further comprising a transmembrane domain? Is the CD28 transmembrane domain itself the CD28 signaling domain? The scope of the claim is unclear and indefinite. Claim 16 is indefinite for the same reasons, since SEQ ID NO: 24 comprises a CD28 signaling domain sequence, but also comprises a transmembrane domain sequence.
Claims 21-22 are indefinite in the recitation of an “N-terminal IL15RA polypeptide”. Does the N-terminal limitation refer to the position of the IL15RA polypeptide with respect to the other elements, such as the IL-15 polypeptide? Does it refer to the N-terminal portion of an IL-15RA polypeptide?
Applicant’s arguments filed 9/14/26 have been fully considered, but they are not persuasive.
Regarding claim 15, Applicant argues that the claim is clear because one skilled in the art would recognize that the CD28 signaling domain comprises a transmembrane domain.
A signaling domain is not a transmembrane domain, and the claim is unclear for the reasons of record. Applicant could amend claim 15 to recite that the CAR comprises a CD28 transmembrane domain and a CD28 signaling domain, for example. It is noted that Claim 16 is also indefinite since as noted above, SEQ ID NO: 24 comprises not only a CD28 signaling sequence but a CD28 transmembrane sequence. It is not clear if the claim encompasses only the CD28 signaling sequence from claim 24 (i.e. a subsequence from claim 24), or whether the claim requires SEQ ID NO: 24 with both signaling and transmembrane. Amendment to recite that the CAR comprises a CD28 transmembrane and CD28 signaling domain according to claim 24, for example, would be remedial.
Regarding claims 21-22, Applicant argues that the amendment to claim 20 overcomes the rejection. This is persuasive in regard to claim 20, however, claims 21-22 have not been amended and stand rejected for the reasons set forth above.
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.
Claim(s) 1-3, 5-6, 10, 13-15, 22, 24-26, and 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/165228, in view of WO2019/148006 and Hurton, 2016 (all of record).
WO 2018/165228 teaches a recombinant nucleic acid construct comprising a first nucleic acid region encoding a CAR, a second nucleic acid region encoding a checkpoint inhibitory dominant negative PD-1 polypeptide see Fig. 10 and 11, and pages 10-12in particular). WO 2018/165228 teaches a T cell genetically modified with said nucleic acids (See page 16, in particular). WO 2018/165228 teaches that the CAR comprises an antigen binding domain that binds to CD44, a transmembrane domain, and CD3 and CD28 intracellular domain (See pages 52-58, in particular). WO 2018/165228 teaches that the CAR can comprise a spacer region that is CH2CH3 of IgG (See page 62, in particular). WO 2018/165228 teaches that the CAR comprises an scFV antigen binding domain targeting CD44 (see pages 53 75, in particular). WO 2018/165228 teaches that expression of the nucleic acid encoding the CAR, the checkpoint and the cytokine is under the control of a constitutive promotor (See page 10, in particular). WO 2018/165228 teaches that the nucleic acid encodes a P2A cleavage site between the CAR and the checkpoint polypeptide, providing for mulitcistronic expression, i.e. via a multicistronic mRNA (see pages 10-12 and Figs 10, in particular). WO 2018/165228 does that the cell further expresses a nucleic acid encoding a suicide gene (see paragraph 80, in particular). WO 2018/165228 teaches a dominant negative PD1 comprising a deletion of the intracellular domain of the PD1 of SEQ ID NO: 33 (See paragraph 82 and 319, in particular).
The references differ from the claimed invention in that it does not explicitly teach IL-15RA/IL-15 or CD44v6.
WO2019/148006 teaches a splice variant of CD44, CD44v6 that is an excellent target for CAR T cell therapy since it is more specifically expressed on malignant cells as compared to CD44. WO2019/148006 teaches an scFV that binds CD44v6 for use in CAR constructs.
Hurton teaches that CAR T cells can be engineered to further express a cytokine such as a membrane form of IL-15, which improves T cell persistence. Hurton teaches that the membrane bound IL-15 comprises a signal peptide, IL-15, Ser-Gly linker (i.e. linking loop sequence), and IL-15RA polypeptide (See Fig. 1, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made include a nucleic acid encoding IL-15/RA/Il-15 polypeptide, as taught by Hurton, in the nucleic acid constructs made obvious by WO 2018/165228 and WO2019/148006. The ordinary artisan at the time the invention was made would have Hurton teaches that CAR T cells can be engineered to further express a cytokine such as a membrane form of IL-15, which improves T cell persistence. Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use the CAR targeting CD44v6, as taught by WO2019/148006, as the CD44 CAR in the constructs taught by WO 2018/165228. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because WO2019/148006 teach CD44v6 is splice variant of CD44 that is an excellent target for CAR T cell therapy since it is more specifically expressed on malignant cells as compared to CD44.
Applicant’s arguments filed 9/14/26 have been fully considered, but they are not persuasive.
Applicant argues that a combination of dominant negative truncated PD-1 and IL-15/IL-15RA cytokine provides unexpected synergistic results in Fig. 4 and 6.
The data in Fig. 4 and 6 is not persuasive of unexpected results for several reasons.
The results are not commensurate in scope with the instant claims. For example, claim 1 encompass any CAR and broadly encompass any IL-15 or IL-15RA. Fig. 4 employs a CEA CAR and a fusion polypeptide comprising both IL-15 and IL-15RA. Fig. 6 does not use any type of cytokine and is a comparison of CD44v6 CAR alone or with PD-1 dominant negative.
Additionally, in Fig. 4 no comparison is made to IL-15/RA alone and it cannot be established whether this is synergistic or merely additive effect. Applicant has also not explained how this is a comparison with the closest prior art. Furthermore, the results are not unexpected. For example, in Fig. 4, the cells comprising IL-15R15 exhibit 30% activation, however, at least 30% of the CAR T cells expressing the IL-15 construct in Hurton are also activated, as measured by STAT5 expression (see Fig. 1). In other words, the ability of IL-15 to activate CAR T cells is an expected beneficial result.
Regarding the date in Fig. 6, this demonstrates that checkpoint inhibitor increased activation of CAR T cells, but this is an expected result. For example, WO 2018/165228 teaches that checkpoint blockade leads to increased T cell activation. Fig. 6 also contradicts Applicant’s’ arguments regarding the unexpected synergy of IL-15 combined with PD-1 dominant negative. For example, the asserted synergistic effect in Fig. 4 is 30% activation with IL-15, a CEA CAR, and PD1dn, however, in Fig. 6, CD44v6CAR and checkpoint inhibition achieves 80% activation, even without IL-15.
Applicant further argues that WO 2018/165228 presents membrane bound IL-12 as a complete and beneficial solution and there would be no motivated to replace it.
The rejection does not rely on replacing IL-12 (although it would be obvious to do so). For example, WO 2018/165228 teaches embodiments of a nucleic acid construct encoding a CAR and a dominant negative PD-1 without IL-12 (see Fig. 1, for example). The ordinary artisan would be motivated to include the IL-15 construct of Hurton, since it teaches that doing so improves persistence of CAR T cells..
Furthermore, it would also be obvious to include said IL-15 in the CAR T cells that include IL-12 and PD-1 dominant negative of WO 2018/165228. For example, WO 2018/165228 teaches that IL-12 acts as an anti-cancer agent (see paragraph 347), and one would include both of said IL-12 and said IL-15 to provide both advantageous effects, i.e. the anti-cancer effect of IL-12 and the T cell persistence effect of Il-15.
Claim(s) 1-3, 5-6, 10, 13, 20-21, 24-26, and 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/165228, in view of Hurton, 2016 and 20150359853.
The teachings of WO 2018/165228 are described above.
The reference differs from the claimed invention in that it does not explicitly teach IL-15RA/IL-15.
Hurton teaches that CAR T cells can be engineered to further express a cytokine such as a membrane form of IL-15, which improves T cell persistence. Hurton teaches that the membrane bound IL-15 comprises a signal peptide, IL-15, Ser-Gly linker (linking loop), and IL-15RA polypeptide (See Fig. 1, in particular).
The ‘853 publication teaches IL-15RA/IL-15 fusion proteins that are expressed with a signal peptide. The ‘853 publication also teaches the sequences of human IL-15RA and human IL-15 for use in the fusion constructs. (see Fig. 1 and 2). Said IL-15Ra and IL-15 comprise sequences 100% identical to SEQ ID NO: 30 and 32 of the instant application. For example, residues 54-162 of the human IL-15 of the ‘853 publication is 100% identical to SEQ ID NO: 32 of the instant application.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made include a nucleic acid encoding IL-15/RA/Il-15 polypeptide, as taught by Hurton, in the nucleic acid constructs taught by WO 2018/165228. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, since Hurton teaches that CAR T cells can be engineered to further express a cytokine such as a membrane form of IL-15, which improves T cell persistence. It would be obvious to use the signal peptide and the human IL-15/IL-15RA sequences taught in the ‘853 publication, as the signal sequence and IL-15RA/IL-15 in the membrane form of IL-15 in the constructs taught by Hurton, since it would involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
Claim(s) 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/165228, WO2019/148006 and Hurton, 2016, as applied to claims 1 and 25 above, in further in view of WO2019038368 and US 20210284965.
The teachings of WO 2018/165228, WO2019/148006 and Hurton, are described above.
The reference differs from the claimed invention in that it does not explicitly teach an IPSC
WO2019038368 teach that cells for CAR genetic modification include IPSC, which are advantageous since IPSC lines can be genetically engineered with a CAR nucleic acid to provide a renewable source for consistently and repeated manufacture of T cells (see page 35, in particular).
The ‘965 publication teaches that available IPSC cell lines include ND50039, which has been produced according to good manufacturing practice (see paragraph 20 and 53, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use an IPSC, as taught by
WO2019038368 and the ‘965 publication, as the cell for genetic modification with the constructs made obvious by WO 2018/165228, WO2019/148006 and Hurton. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because WO2019038368 teach that IPSC lines can be genetically engineered with a CAR nucleic acid to provide a renewable source for consistently and repeated manufacture of T cells. Furthermore, the ordinary artisan would be particularly motivated to select ND50039 as the IPSC cell line, since the ‘935 publication teaches that it is produced according to good manufacturing practice. Additionally, selecting from known and available IPSC cell lines would involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
The following are new grounds of rejection necessitated by Applicant’s claim amendments.
Claims 5, 16, 21, and 24 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 5 is directed to a “nucleic acid expression construct” wherein the nucleic acid are configured “as a polycistronic mRNA”. It is unclear if the claims require that the nucleic acid construct is an mRNA construct, or if the claims would encompass a DNA expression construct that is configured such that is it expressed (i.e. transcribed) as a polycistronic mRNA. If the former interpretation is desired, Applicant could amend claim 5 to recite wherein the recombination nucleic acid construct is an mRNA, for example. If the latter interpretation is desired, Applicant could amend claim 5 to recite that the nucleic acid is configured to be expressed as a polycistronic mRNA, for example.
Claim 16 is indefinite since it recites a signal sequence according to “SEQ ID NO”. It is not clear what SEQ ID Nos are encompassed.
Claim 21 is indefinite for the same reasons as claim 16. It recites a signal sequence and a linking loop according to “SEQ ID NO”. For the purposes of applying prior art, the claim is being interpreted as encompassing any signal sequence or linking loop sequence.
Claim 24 is indefinite in the recitation of a “chimeric polypeptide” encoded by a recombinant nucleic acid expression construct comprising a sequence encoding a CAR, a dominant negative PD1 and IL-15 and/or IL-15RA. The claim appears to be directed to a single chimeric polypeptide comprising each of the protein components, i.e. a chimeric polypeptide comprising a CAR, dominant negative PD1 and IL-15 and/or IL-15RA. The instant specification discloses nucleic acid constructs encoding the three components that is expressed as a polycistronic mRNA wherein the components are separated by a polypeptide cleavage site such as P2A. Such polycistronic mRNA with cleavage sites such as P2A are used in the art to encode multiple (separate) proteins from a single mRNA, wherein the ribosome skips the P2A cleavage site. It is not clear if the claim would encompass separate proteins each encoded by such a polycistronic mRNA, or whether the claims require a single chimeric (fusion) protein comprising each of the three proteins encoded by the nucleic acid sequence regions. For the purposes of applying prior art, claim 24 is being interpreted as encompassing a CAR, truncated PD1, and IL-15 and/or IL-15RA as encoded by a nucleic acid that is expressed as a polycistronic mRNA wherein the components are separated by a polypeptide cleavage site such as P2A
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 20 and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The specification and the claims as originally filed do not provide support for the invention as now claimed, specifically:
“A chimeric polypeptide” encoded by a recombinant nucleic acid sequence which encodes comprises a CAR, a dominant negative PD1 and a immune stimulatory cytokine (claim 24)
B), A construct comprising a signal sequence, a soluble “N-terminally located” extracellular domain of the IL-15RA, a linking loop, and an IL-15 polypeptide (claim 20).
It is noted that applicant has not cited any support for the new limitation in the specification. A review of the specification fails to reveal support for the new limitations.
Regarding A), the present claim encompass a fusion protein comprising a CAR, dominant negative PD1 and cytokine, i.e. a single chimeric polypeptide comprising the three encoded components. The specification discloses nucleic acids encoding the three components, and discloses that they can be encoding as a polycistronic mRNA wherein the components are separated by a polypeptide cleavage site such as P2A. Such polycistronic mRNA with cleavage sites such as P2A are used in the art to encode multiple (separate) proteins from a single mRNA, wherein the ribosome skips the P2A cleavage site. This is also what is exemplified in the instant specification. They do not encode a chimeric polypeptide comprising all three components, as broadly encompassed by claim 24. The specification did not contemplate a “chimeric polypeptide” comprising a CAR, a PD1 polypeptide, and an IL-15 and/or IL-15RA, as recited in the present claim.
Regarding B), the specification on page 52 discloses IL-15RA N-terminal 120 amino acids, and discloses an example of an IL-15 fusion protein wherein the elements are arranged in order from N-terminus to C-terminus: signal peptide, IL-15RA, linking loop, IL-15 (i.e. IL15R15 used in the examples on p. 56). However, the present claims would encompass a polypeptide wherein IL-15RA is N-terminal to the signal peptide, for example, which is not contemplated by the instant specification. Furthermore, the specification does not disclose a “soluble” IL-15RA receptor, as broadly recited in the present claims. The specific example of the N-terminal 120 amino acids of IL15RA, i.e. SEQ ID NO: 30, does not have the same scope as any “soluble” IL-15RA polypeptide.
Claim(s) 1-2, 5-6, 10, 13-15, 19, 24-26, and 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/086989, in view of WO 2018/165228 (of record).
WO 2020/086989 teaches a nucleic acid encoding a CAR, a nucleic acid encoding a dominant negative truncated PD-1, and a nucleic acid encoding a therapeutic agent, such as IL-15, that are introduced into a T cell (see claims 25- 63, 66 and page 28-32, in particular). WO 2020/086989 teaches that the CAR comprises an extracellular scFV, a transmembrane domain, and an intracellular CD3 and CD28 co-stimulatory domain, and the CAR targeting CD44v6 (see entire document and paragraph 127, in particular). WO 2020/086989 teaches nucleic acid sequences encoding dominant negative PD-1 comprising SEQ ID NO: 59. Said SEQ ID NO: 59 comprises a sequence 100% identical to SEQ ID NO: 28 of the instant application. WO 2020/086989 teaches pharmaceutical compositions.
Although WO 2020/086989 does not explicitly teach a nucleic acid expression construct comprising each of the nucleic acids, it would be obvious to provide them on a single nucleic acid construct using P2A cleavage sites configured for multicistronic mRNA expression as taught by WO 2018/165228, as a matter of convenience (see pages 10-12 and Figs 10, in particular). It would also be obvious to include a suicide gene for safety as taught by WO 2018/165228.
Claim 19 is rejected under 35 U.S.C. 103(a) as being unpatentable over WO 2018/165228, WO2019/148006, and Hurton, 2016, as applied to claims 1, 5 above, and further in view of WO 2020/086989.
The combined teachings of WO 2018/165228, WO2019/148006, and Hurtonare discussed above.
They do not explicitly teach that the nucleic acid construct comprising a nucleic acid sequence encoding a dominant negative PD1 according to SEQ ID NO: 28.
WO 2020/086989 teaches nucleic acid sequences encoding dominant negative PD-1 comprising SEQ ID NO: 59, which lacks an intracellular domain and can be expressed in CAR T cells. Said SEQ I DNO: 59 comprises a sequence 100% identical to SEQ ID NO: 28 of the instant application.
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was made to apply the teachings of WO 2020/086989, to the dominant negative PD1 in the constructs of WO 2018/165228, WO2019/148006, and Hurton. Selecting from known dominant PD1 constructs would involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
Claims 11-12 are rejected under 35 U.S.C. 103(a) as being unpatentable over WO 2018/165228, WO2019/148006, and Hurton, as applied to claims 1, 5 above, and further in view of US 20190038671.
The combined teachings of WO 2018/165228, WO2019/148006 and Hurton, are discussed above.
They do not explicitly teach that a nucleic acid encoding CCR4.
The ‘671 publication teaches expressing CCR4 in CAR T cells along with a checkpoint inhibitor to improve homing, wherein the CCR4 is expressing recombinantly
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was made to apply the teachings of the ‘671 publication, to the constructs of WO 2018/165228, WO2019/148006, and Hurton. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since the ‘671 publication teaches that including CCR4 improves CAR T cell homing.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 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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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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