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 .
Election/Restrictions
Applicant’s election of species SEQ ID NO: 72, SEQ ID NO: 119, SEQ ID NO: 96, SEQ ID NO: 140 and SEQ ID NO: 137 in the reply filed on 5/8/2016 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Applicant did not make an election between SEQ ID NO: 149 and 152. Both sequences have been searched.
Specification
The use of the term “Glutamax” and “CliniMacs”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 87 and 129 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 87 contains the trademark/trade name Sleeping Beauty transposon, piggyBac transposon, TcBuster transposon and Tol2 transposon. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe transposon sequences, and, accordingly, the identification/description is indefinite.
Regarding claim 129, the recitation of “a method of treating cancer or autoimmune disease or disorder” renders the claim indefinite because it is unclear whether the claim is directed to a method of treating cancer, autoimmune disease or autoimmune disorder, or a method of treating cancer, autoimmune disease or any type of disorder.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 84, 86, 87 and 109 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for recombinant vector that comprises a polycistronic expression cassette comprises a transcriptional regulatory element link to a polynucleotide having 100% identity to SEQ ID NO: 149 or encodes an amino acid sequence having 100% identity with SEQ ID NO: 152, and a method of producing a cell that comprise said recombinant vector and a DNA transposase, does not reasonably provide enablement for polynucleotide sequence having 75% and above homology with SEQ ID NO: 149, or encodes an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 152. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
The nature of the invention
The claimed invention of claim 84 is a recombinant vector that comprises a polynucleotide expression cassette that comprises a transcription regulatory element operably linked to a polynucleotide at least 75% identical to SEQ ID NO: 149 or a polynucleotide encoding an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 152. Dependent claims 86 and 87 further adding left and right ITR of a DNA transposon to said recombinant vector, wherein claim is directed to a method of producing a population of cells comprising introducing said vector and a DNA transposase into a population of cells.
The breadth of the claim
The scope of claim encompasses expression cassette that comprises polynucleotides having 75% sequence identity with SEQ ID NO: 149 (about 902bp variation) and amino acid having 95% identity with SEQ ID NO: 152 (about 60 aa variation).
The teaching from the specification and the presence of working examples
The specification teaches that SEQ ID NO: 149 is cassette 1 from plasmid A and D, which encodes CD19CAR-F2A-mbIL15-T2A-HER1t (Table 10). The specification teaches SEQ ID NO: 152 is translation of expression cassette from plasmid A and D that encodes CD19CAR-F2A-mbIL15-T2A-HER1t (Table 11). Both plasmid A and D are tricistronic sleeping beauty plasmids, they expresses mbIL15, CD19CAR and HER1t in donor cells, and demonstrates efficient and uniform co-expression of all three transgenes (Example 2, page 141, paragraph [00353]). The specification demonstrates in example 3 that additional donor cells also show improved co-expression with the use of plasmid A and D, which share the same transgene order (page 144, paragraph [00363]), and also has nearly identical integration numbers for all three transgenes (paragraph [00368]). The specification also demonstrates improved overall survival of mouse tumor model without toxicity when cells transfected with plasmid A is administered in vivo (section 6.4.2.4). However, the specification does not demonstrate any other tricistronic expression cassette having sequence 75% and above with SEQ ID NO: 149 or 95% and above with SEQ ID NO: 152 that achieves same expression efficiency, integration efficiency and anti-tumor activity in vitro and/or in vivo. The specification does not teach what type of modification to nucleotide sequence (SEQ ID NO: 149) or amino acid sequence (SEQ ID NO: 152) would be tolerated, or improving the expression and activity of cells expressing CAR19, mIL-15 and Her1t. As such, the scope of the claim exceeds the teaching from the instant specification.
The state of prior art and the predictability in the prior art
A search of the sequence SEQ ID NO: 149 and SEQ ID NO: 152 does not reveal any prior art sequence that has 75% and above identity with SEQ ID NO: 149 and 95% and above identity with SEQ ID NO: 152, even though individual components within plasmid A (CD19CAR, mbIL15 and HER1t) is known in the art. As suggested in the specification, the novelty and improvement of the recombinant vector expressing CD19CAR-mbIL-15-HER1t is the overall sequence and the order of said sequences when expressing the fusion polypeptide. Since there is no information provided in prior art to which part of the modification of said expression cassette as contained in plasmid A and D may still retain the same function of said polypeptide, whether sequences comprising nucleotide or amino acid variation that having 75% and above identity with SEQ ID NO: 149 and 95% and above identity with SEQ ID NO: 152 still has the same function is unpredictable.
The amount of experimentation required to make/use the invention
Both specification and prior art does not teach whether sequence variation of SEQ ID NO: 149 and SEQ ID NO: 152 would still retain the function of the expression cassette contained within plasmid A and D. A skilled artisan would have to determine which and how many nucleotide modification (up to 902bp out of 3608bp), and amino acid modification (up to 60 aa out of 1200 aa) can be made, and also why type of modification may be made without affecting the efficiency of expression of the transcript as well as the anti-tumor activity in vivo when expressed in immune cells. A skilled artisan would have to engage in undue experimentation to determine the sequence variation claimed in claim 84 (and dependent claims thereof) without teaching from the instant specification, and guidance from prior art. Therefore, the claimed recombinant vector is only enabled to the scope as indicated above.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 6, 10, 23, 26, 30, 33, 43, 48, 57, 59, 94 and 129 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rezvani (WO 2020/106621), in view of Shah (WO 2017/214333).
Claim 1 is drawn to a recombinant vector comprising a polycistronic expression cassette comprises a transcriptional regulatory element operably linked to a polynucleotide that comprises: a polynucleotide sequences that encodes a chimeric antigen receptor (CAR) that comprises an extracellular antigen-binding domain that specifically binds to CD19, a transmembrane domain and a cytoplasmic domain; a second polynucleotide sequence that comprises an F2A element; a third polynucleotide sequence that encodes a fusion protein that comprises IL-15 and IL-15Rα, functional fragment or variant thereof; a fourth polynucleotide that comprises a T2A element; and a fifth polynucleotide sequence that encodes a marker protein.
Rezvani teaches a polycistronic vector for CAR and TCR transduction that comprises expression cassette that comprises multiple cistrons and linked by multiple 2A element, including T2A, E2A, F2A and/or P2A and transcriptional regulatory element (Figure 1A, paragraph [0006], [0009], [0011] and [0067]). Rezvani teaches the CAR comprises at least an intracellular signaling domain, a transmembrane domain and an extracellular domain, wherein the extracellular antigen binding domain that binds to CD19 (paragraph [0083], [0090]). Rezvani teaches that CAR may be co-expressed with a cytokine to improve persistence when there is low amount of tumor associated antigen, wherein said cytokine includes IL-15 (paragraph [0090]). Rezvani also teaches that vector encodes CAR may also comprise a marker protein (paragraph [0078]).
The teaching from Rezvani differs from claim 1 is that Rezvani does not specifically teach IL-15 is a fusion protein that comprises IL-15, and IL15-Rα or functional fragment or variant thereof.
Shah teaches CAR targeting CD33, and vectors expressing said CAR ([0009] and [0010]). Shah teaches cytokines may be co-expressed with a cell that expresses the CAR, wherein said cytokine may be a fusion of IL-15 and IL-15Rα, wherein IL-15 and IL-15Rα is indirectly through a linker (paragraph [00192]). Shah teaches the mbIL-15 comprises amino acid sequence having at least 90%-100% identity with the amino acid sequence of SEQ ID NO: 37 (paragraph [00193]). SEQ ID NO: 37 (disclosed by Shah) has 100% homology with SEQ ID NO: 119 of present application (see alignment attached).
It would have been obvious to an ordinary skilled in the art to use the IL-15 and IL-15Rα fusion as the cytokine in the polycistronic vector to produce CAR as taught by Rezvani, because it is a prior art known cytokine in the form of a fusion for enhance CAR-T cell function as demonstrated by Shah. Cloning a prior art known cytokine into the polycistronic vector would have been routine experimentation and within the capability of an ordinary skilled in the art. Therefore, the claimed invention of claim 1, 45, 46 and 59 would have been prima facie obvious at the time the application was filed.
Regarding claim 2, Rezvani teaches the sequence F2A, SEQ ID NO: 4, which is 100% identical to a sequence comprised in SEQ ID NO: 137 of present application (page 18, line 3).
Regarding claim 6, Rezvani teaches the sequence T2A that comprises SEQ ID NO: 1, which is 100% identical to SEQ ID NO: 140 (page 17, last line).
Regarding claim 10, Rezvani teaches the antigen binding domain comprises a heavy chain variable region and a light chain variable region (paragraph [0089]), wherein VH and VL inherently comprises CDR1-3.
Regarding claim 23, Rezvani teaches the CAR further comprises a hinge region between antigen binding domain and transmembrane domain (paragraph [0087]).
Regarding claim 26, it would have been obvious to an ordinary skilled in the art to use a prior art known transmembrane domain such as CD8 transmembrane domain in the CAR construct rendered obvious by combined teaching from Rezvani (paragraph [0095]) and Shah, as evidenced by the sequence BDA14677, which is 100% identical to the present claimed SEQ ID NO: 43 (see attached alignment).
Regarding claim 30 and 33, Rezvani teaches the cytoplasmic domain comprises a signal domain CD3ζ and a co-stimulatory domain CD28, 4-1BB, OX-40 (paragraph [0088]).
Regarding claim 43, it would have been obvious to an ordinary skilled in the art to use a construct that encodes a CAR having sequence 100% identical to SEQ ID NO: 72 based on the combined teaching from Rezvani and Shah, because it is a prior art known sequence encoding CD19 specific CAR, that comprises CD19 scFv-CD8a-CD28-CD3z) with signal peptide as evidenced by the sequence BFM30222 (see sequence alignment).
Regarding claim 48, Shah teaches a marker protein that is a truncated HER1 or a variant thereof (paragraph [00177]).
Regarding claim 57, it would have been obvious to an ordinary skilled in the art to use the marker protein comprises a marker protein having 100% sequence identity to SEQ ID NO: 96 based on the combined teaching from Rezvani and Shah, as evidenced by sequence BFX07237 (see attached alignment), which teaches membrane bound IL-1.T2A.HER1T1 fusion protein construct.
Regarding claim 94, Rezvani teaches immune cells transfected with the polycistronic vector that expresses CAR and other components (paragraph [00134]).
Regarding claim 129, Rezvani teaches the immune cells expressing CAR and other component may be used to treat cancer or other immune disorders (paragraph [00139]).
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CELINE X QIAN/Primary Examiner, Art Unit 1637
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