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 1,3-4, and 7 are amended.
Claim 6 is canceled.
Claims 1-5 are under examination.
Withdrawn Rejections
Rejections under - 35 USC § 103
The rejection of claims 1-5 under 35 U.S.C. 103 as being unpatentable over Loew et al (WO 2016/098078 A2) in view of Wu et al (Science, 2015) is withdrawn in view of claims amendment.
Response to Amendment
Applicant’s arguments have been carefully considered and found persuasive. The new ground of rejection below addresses the deficiencies raised by Applicant with respect to the amended claims.
New Grounds of Rejections
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 4 is 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 4 recites the limitation “ the caged inducer comprises caged abscisic acid (ABA), caged gibberellic acid (GA), or caged rapamycin”. There is insufficient antecedent basis for this limitation in the claim. For examination purpose, the limitation is interpreted to belong to claim 1.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 are rejected under 35 U.S.C. 103 as being unpatentable over Loew et al (WO 2016/098078 A2) in view of Wu et al (Science, 2015), and Liang et al ( US 2017 /0226595 A1).
Regarding claims 1-5, Loew et al disclose gene editing systems comprising of dimerization switches that allow for the regulation of a gene editing function by administering, for example, an inducer. (See abstract). Loew et al utilize dimerization switches comprising of FKBP-FRB based system that dimerizes in the presence of rapamycin (i.e. the inducer). The FKBP-FRB dimerization system consists of an FK506 binding protein (FKBP) domain (i.e. first switch domain) and the FKBP-rapamycin binding domain (FRB) (i.e. second switch domain) that heterodimerize in the presence of the rapamycin, this reads on claims 3 and 4.( See page 14, lines 3-6, and lines 11-19). It should be noted that the FKBP-FRB based dimerization system reads on the chemical induced proximity complex (CIP) expression system term used in instant claims. Loew et al also demonstrate that the FRB-derived switch domain can be fused to a transactivation domain of a transcription factor (e.g. the transactivation domain of the NFkB p65 transcription factor), and the FKBP derived switch domain can be fused to DNA binding domain of a transcription factor (e.g. ZFHDl of the Zif268 transcription factor).( See page 69, lines 1-9 and 19-23). Loew et al state that “ the first and second switch domains coupled to the transcription factor domains are introduced, e.g., to a cell, by introducing nucleic acids, e.g., one or more vectors, encoding the first and second switch domains coupled to the transcription factor domains and causing said first and second switch domains coupled to the transcription factor domains to be expressed), this reads on the second component of claim 1. (See page 69, lines 15-). Loew et al also teach a transgene (i.e. a polynucleotide) that is operably linked to a promoter, wherein the upstream region of the promoter contains a plurality of ZFHD1 binding sites (i.e. a regulatory region inducible by an inducer), this reads on the first component of claim1. (See page 69, lines 23-25). Loew et al teach that the transgene can encode for any therapeutic protein. (See page 70, lines 8-11). Loew et al state that “ Upon administration of the dimerization molecule (e.g. rapamycin/inducer) the transactivation domain and DNA binding domain of the transcription factors coupled to the FKBP and FRB derived switch domains can associate. The ZFHDl DNA binding domain bind to the ZFHDl binding sites located upstream of the desired transgene, and the transactivation domain is in sufficient proximity to initiate transcription of the transgene”, this reads on claim 2. ( See page 69 (Line 26), and page 70 (lines 1-4). Loew et al also disclose that the gene editing system comprising the gene editing dimerization switch can be used to create an allogeneic immune cell, e.g., a T-cell. (See page 94, lines 3-4). Loew et al further disclose that the gene editing system can be used to regulate expression of two or more genes. (See page 94, lines 29-31). Loew et al also suggest that the gene editing system can be utilized to decrease off-target side effects, and to increase therapeutic window. (See page 46, lines 7-8).
However, Loew et al do not teach a polynucleotide that encodes a chimeric antigen receptor (CAR), wherein the CAR is a split CAR (i.e. claim 5).
Wu et al disclose that the use of T-cell expressing conventional CAR exhibit excessive activity that is difficult to control and can cause severe toxicity. To overcome this, Wu et al developed a split CAR (also termed “ON-switch CAR” ) that requires both an antigen and small molecule to fully activate the T cell. Wu et al disclose that the strategy for constructing a split CAR design includes splitting the conventional CAR into two physically separate polypeptides comprising antigen-binding component and intracellular signaling component that can be conditionally reassembled when a heterodimerizing small-molecule agent is present (i.e. an inducer). Wu et al state that “ This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity”. (See abstract and Fig.1C). Wu et al disclose that the two parts of the split receptor are fused to heterodimerization domains that conditionally interact upon binding of a heterodimerizing small molecule (i.e. inducer). (See page 2, 3rd column, lines 3-6). Wu et al teach that the heterodimerization components include the FKBP-FRB that heterodimerize in the presence of the rapamycin analog AP21967 (also termed rapalog). (See page 4, 1st column, lines 2-6). Wu et al disclose that the use of the ON-switch CAR (i.e. split CAR) generate a safer therapeutic cells that tightly integrate cell autonomous recognition and user control. (See abstract).
Neither Loew nor Wu teach a CIP complex regulated by a caged inducer.
Liang et al teach a CIP complex comprising of dimerization switches that allow for the regulation of a gene editing function by administering, for example, an inducer. ( See abstract). The gene editing system of Liang et al comprises of dimerization switches that dimerize in the presence of a caged inducer, wherein the caged inducer can be activated by chemical or physical stimuli such as H2O2, light, or Fe2+. ( See abstract, and paragraphs [0003], [0085-0086]). Liang et al also teach that the inducer can include a caged ABA or GA. ( See paragraphs [0004], [0051], and [0056-0057], and [0064]). In another embodiment, Liang et al also teach a cell comprising the CIP complex and a polynucleotide whose expression is controlled by the CIP complex (i.e. the dimerization switches and the caged inducer). Liang et al further teach that the polynucleotide regulated by the CIP complex might be either endogenous or exogenous to the cell. ( See paragraph [0007] and claim 7). According to Liang et al, the modified CIP complex can be used to control cellular processes such as gene transcription, protein translocation, signal transduction, and/or cytoskeleton remodeling.[0089]. Liang et al further state that “ This new strategy can be a useful tool for synthetic biologists and ultimately can be applicable to the development of gene and cell therapies”. ( See paragraph [0051]).
Taken together, claim 1 is combining prior art elements according to known methods to yield predictable results, namely the predictable results being the use of gene editing systems comprising of dimerization switches and caged inducer for the development of a modified and precision-controlled therapeutic T cells. Because Loew et al teach that the gene editing system comprising of FKBP-FRB that heterodimerize in the presence of an inducer, such as rapamycin, can be used to create a modified allogenic T cell, and to regulate the expression of one or more gene in the attempt to decrease off-target effect and increase therapeutic window, but fail to teach a modified CIP complex utilizing a caged inducer and a T cell comprising a split CAR . Wu et al utilized the FKBP-FRB based system that heterodimerizes in the presence of a rapamycin analog to engineer a T cell expressing a split CAR, rather than a conventional CAR, in an attempt to provide the user a control over the dose and timing of T cells therapy. Liang et al teach a cell comprising a modified CIP complex directing the controlled expression of an exogenous or endogenous polynucleotide within a cell, and directly suggest that the modified CIP complex can be utilized in the development of gene and cell therapies. An ordinary skill in the art who had viewed Loew and Wu, could have come across Liang and immediately noticed the strong possibility of employing the modified CIP complex, instead of the conventional one taught by Loew and Wu, to engineer a modified T-cell comprising a therapeutic polypeptide and split CAR under the control of the modified CIP complex. One with ordinary skill in the art would have been motivated to do so because it would generate a safer and a precision-controlled therapeutic T cells.
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 1-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-14 of U.S. Patent No. 10,907,219 in view of over Loew et al (WO 2016/098078 A2), Wu et al (Science, 2015), and Liang et al.
Regarding claims 1-5, The claims of U.S. Patent No.’219 teach a modified CIP complex comprising of dimerization switches and a caged inducer. The claims also teach a cell comprising the modified CIP complex, and a polynucleotide whose expression is regulated by the modified CIP complex. The claims further teach that the polynucleotide regulated by the CIP complex can be either endogenous or exogenous to the cell. Taken together, the claims of U.S. Patent No.’219 teach a cell comprising a polynucleotide, wherein the expression of the polynucleotide is controlled by the modified CIP complex. However, the claims do not teach a T-cell that express a split CAR.
The teachings of Loew, Wu, and Liang are set forth above.
Therefore, it would have been prima facie obvious at the time the invention was filed to one skilled in the art to combine the teachings of the U.s patent No. 10,907,219, Loew, Wu, and Liang to generate a modified and precision-controlled therapeutic T cells using the system of claim 1. Because U.S patent No. 10,907,219 teaches a cell comprising a polynucleotide, the expression of which is controlled by a modified CIP complex regulated by a caged inducer, but it fails to teach a modified T-cell expressing a split CAR under the control of a modified CIP complex. Loew et al teach a gene editing system comprising of FKBP-FRB that heterodimerize in the presence of an inducer, such as rapamycin, can be used to create a modified allogenic T cell, and to regulate the expression of one or more gene in the attempt to decrease off-target effect and increase therapeutic window, but fail to teach a modified CIP complex utilizing a caged inducer or a T cell comprising a split CAR . Wu et al utilized the FKBP-FRB based system that heterodimerize in the presence of rapamycin analog to engineer a T cell expressing a split CAR, instead of the conventional CAR, in the attempt to provide the user a control over the dose and timing of T cell therapy. Liang et al teach a cell comprising a modified CIP complex controlling the expression of an exogenous or endogenous polynucleotide within the cell, and directly suggest that the modified CIP complex can be utilized in the development of gene and cell therapies. Thus, one with ordinary skill in the art would have been motivated to combine the teachings of prior arts in combination of US patent No.‘219 to engineer a system comprising a caged inducer and the T-cell of claim 1 since doing so would yield a safer and a more precisely controlled therapeutic T cells. Combining prior art elements according to known methods to yield predictable results. See MPEP 2143 (I)(A).
Response to Arguments
Applicant's arguments filed 07/17/2025 have been fully considered but they are not
persuasive.
Applicants argue that claim 1 recites a system comprising a T cell that has an additional layer of control over T cell activity compared to the T cell produced by combining the teachings of Loew and Wu.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because Applicants amended claim 1 to recite a system that includes a caged inducer compound in addition to the T cell previously recited in claim 1, while Loew in view of Wu do not teach a system that includes a T cell and a caged inducer; however, a new ground of rejection is made over Loew in view of Wu and Liang, that covers all of the added claim limitations ( as discussed above).
Applicants further argue that, while the claims of US patent No. “ 10,907,219” describes a stimulus induced proximity (SIP) system using caged inducers that become activated by chemical or physical stimuli, the claims neither suggest or describe incorporating the system into a T cell. The patent claims also do not describe or suggest a T cell comprising a therapeutic protein and a chimeric antigen receptor (CAR) , the expression of which is regulated by the caged inducer.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because while the claims of patent ‘219 do not specifically recite a T cell, the claims are directed to a cell comprising the modified CIP complex and a polynucleotide whose expression is regulated by the modified CIP complex. ( See ‘219 patent claims (4-8)). Under the broadest reasonable interpretation, the breadth of the patent claims are extremely broad, covering a wide range of cells, including T cell. Thus, the argument is not persuasive since an ordinary skill in the art coming across the patent claims can readily envision using the modified CIP complex and engineering a T cell comprising a therapeutic polypeptide whose expression is under the control of the modified CIP complex.
As per the Applicants second argument that the patent claims do not teach the whole invention, for example, do not teach using the modified CIP complex to regulate CAR expression in a T cell or a therapeutic polypeptide. This is not found persuasive because Applicants appear to argue references individually. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Taken together, an ordinary skill in the art coming across the teachings of Loew et al, Wu et al, and the claims of ‘219 would be able to readily envision engineering a system comprising a caged inducer and the T-cell of instant claim 1, since doing so would yield a safer and a more precisely controlled therapeutic T cells.
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 FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638