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 .
The claim listing filed April 13, 2023 is pending.
Claims 9 and 10 are canceled.
Claims 1-8 and 11-13 are pending.
Claim 1 is an independent claim.
Applicant’s election with traverse of Group I (claims 1-8, drawn to a universal CAR-T cell targeting CD19; a method for preparing the universal CAR-T cell targeting CD19; and a pharmaceutical composition comprising the universal CAR-T cell targeting CD19) in the reply filed on January 20, 2026 is acknowledged.
The Applicant traverses this election on the grounds that they disagree that the inventions listed as groups I and II in the Office Action mailed 11/20/2025 do not relate to a single general inventive concept under PCT Rule 13.1. The Applicant argues that given the amendment to claim 1 to further limit the CAR-T cell to a CAR-DNT cell and limit the scFv targeting CD19, groups I-II share the same special technical feature. The Applicant asserts that no prior art has disclosed or hinted the universal CAR-DNT cell targeting CD19 as claimed in the present application. The Applicant asserts that Tan et al. disclose a CD19-CAR-T cell, but not a CD19-CAR-DNT cell. The Applicant further asserts that it is well-known to those skilled in the art that DNT cell is different from T cell. The Applicant further asserts that, thus, those skilled in the art can not readily obtain the claimed universal CAR-DNT cell targeting CD19 based on the disclosure of Tan et al.
The Applicant further argues that those skilled in the art cannot anticipate what technical effects the CD19-CAR-DNT cell with the specific structure of the present application can achieve. The Applicant asserts that Example 4 of the present specification records the cell killing effect of the CAR- DNT cell targeting CD19 (CAR19-DNT cell). The Applicant argues that the CAR-DNT cells of the present application clearly have an extremely superior cell killing effect, which cannot be anticipated by those skilled in the art and therefore, amended claim 1 is patentable over the disclosure of Tan et al.
This is not found persuasive because, while the Examiner agrees that Tan et al. do not disclose a CD19-CAR-DNT cell, that a DNT cell is different from T cell, and that those skilled in the art can not readily obtain the claimed universal CAR-DNT cell targeting CD19 based on the disclosure of Tan et al., it would have been obvious to a skilled artisan to modify the CD19-CAR-T cell taught by Wu and Golubovskaya 2020 (US 20200354451 A1, has an effective filing date of 12/22/2017) into a CD19-CAR-DNT cell based on the teachings of Wu and Golubovskaya in view of Lee et al. 2018 (Clin Cancer Res. 24 (2): 370–382) as is outlined in the 103 rejection below.
Furthermore, contrary to the Applicant’s arguments regarding the superior technical effects achieved by the CD19-CAR-DNT cell with the specific structure of the present application based on Example 4 of the disclosure, it is noted that the cited example compares the cytotoxic activity of DNT cells with and without a CD19CAR. Therefore, this example as most supports the insertion of a CD19CAR into a DNT cell, but it does not distinguish between the killing capacity of a CD19-CAR-T cell and a CD19-CAR-DNT cell since CD19-CAR-T cells were not used in Example 4. Furthermore, skilled artisan would have reasonably expected that a CD19-CAR-DNT would have superior CD19-dependent cytotoxicity to a DNT without a CD19CAR because it would be able to specifically target CD19-expressing cells and activate the underlying DNT cell in a CD19-dependent fashion.
Therefore, in view of the Applicant’s amendment filed 01/20/2026, groups I and II do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the reasons outlined in the 103 rejection below.
Thus, the restriction requirement mailed 11/20/2025 is maintained.
Claims 11-13 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions.
Claims 1-8 are currently under consideration.
Priority
The instant application is a 371 of PCT/CN2021/087311 filed 04/14/2021 and claims foreign priority to CN202010314336.0 filed 04/20/2020.
A translated copy of CN202010314336.0 has not been filed. Therefore, it is not clear if the foreign priority document has adequate support for the instant claims.
Claim Objections
Claims 1-8 are objected to because of the following informalities:
Claims 1 and 5 recite “CD3
ζ
is a cytoplasmic signaling sequence derived from CD3
ζ
; each "-" independently indicates a linking peptide or peptide bond connecting each of the above elements” in lines 14-16 where it should be “CD3
ζ
is a cytoplasmic signaling sequence derived from CD3
ζ
; and each "-" independently indicates a linking peptide or peptide bond connecting each of the above elements.”
Claim 5 recites “A method for preparing a universal CAR-DNT cell targeting CD19 of claim 1” in lines 1 and 2 where it should recite “A method for preparing the universal CAR-DNT cell targeting CD19 of claim 1.”
Claim 5 also recites “CD3𝞯 is a cytoplasmic signaling sequence derived from CD3𝞯; each "-" independently indicates a linking peptide or peptide bond connecting each of the above elements; and (ii) providing a DNT cell culture medium, the cell culture medium containing at least one DNT cell; transducing the expression vector of step (i) into the DNT cell, thereby obtaining the universal CAR-DNT cell targeting CD19” in lines 12-17 where it should recite “CD3𝞯 is a cytoplasmic signaling sequence derived from CD3𝞯; and each "-" independently indicates a linking peptide or peptide bond connecting each of the above elements; and (ii) providing a DNT cell culture medium, the cell culture medium containing at least one DNT cell; and transducing the expression vector of step (i) into the DNT cell, thereby obtaining the universal CAR-DNT cell targeting CD19.”
Claim 8 recites “a universal CAR-DNT cell targeting CD19 of claim 1 or 2” in line 2 where it should recite “the universal CAR-DNT cell targeting CD19 of claim 1 or 2.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Indefinite language
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 1-8 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 1 recites the limitation “wherein the universal CAR-DNT cell expressing an exogenous CAR construct” in lines 1 and 2. However, the preamble of claim 1 recites “A universal CAR-DNT cell targeting CD19” but there is no mention of the CAR-DNT cell “expressing an exogenous CAR construct.” Therefore, the limitation recited in lines 1 and 2 lack antecedent basis. Amending claim 1 to recite “wherein the universal CAR-DNT cell expresses an exogenous CAR construct” would obviate this part of the rejection.
Claim 1 also recites “the single-chain variable region of an antibody targeting CD19” in line 7. However, there is no mention of an anti-CD19 single-chain variable region in claim 1 prior to this limitation. Therefore, the limitation recited in line 7 lacks antecedent basis. Amending claim 1 to recite “a single-chain variable region of an antibody targeting CD19” would obviate this part of the rejection.
Claim 3 recites “wherein the TCR in the universal CAR-T cell is not knocked out” in lines 1 and 2. Claim 3 is dependent on claim 1 which does recite “a TCR” or a “CAR-T cell.” Therefore the phrases “the TCR” and “the universal CAR-T cell” in claim 3 lack antecedent basis. Amending claim 3 to recite “wherein the universal CAR-DNT cell comprises a TCR and wherein the TCR in the universal CAR-DNT cell is not knocked out” would obviate this part of the rejection.
Claim 5 recites “wherein in the DNT cell culture medium, the concentration of the gentamicin is 40-80 units/ml, preferably 60 units/ml, the concentration of the recombinant human interleukin 2 is 150-1000 IU/ml, preferably 200-250 IU/ml, the concentration of the recombinant human interleukin 15 is 5-20 ng/ml, preferably 10 ng/ml, the concentration of the recombinant human interleukin 7 is 1-5 ng/ml, preferably 2 ng/ml, the concentration of the recombinant human interleukin 12 is 5-20 ng/ml, preferably 10 ng/ml, and the concentration of the autologous plasma is 3-25 v%, preferably 10-20 v%; and (iii) optionally detecting the universal CAR-DNT cell obtained in step (ii)” in lines 18-25.
Regarding the recitation of “the gentamicin,” “the recombinant human interleukin 2,” “the recombinant human interleukin 15,” “the recombinant human interleukin 7,” “the recombinant human interleukin 12,” and “the autologous plasma in claim 5, it is noted that claim 5 is dependent on claim 1 which does not recite gentamicin, recombinant human interleukin 2, recombinant human interleukin 15, recombinant human interleukin 7, recombinant human interleukin 12, or autologous plasma. Therefore, these components of the DNT culture medium lack antecedent basis.
Regarding the recitation of the terms “preferably” and “optionally” in claim 5, the phrases “preferably” and "optionally" in lines 19-25 render the claim indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d).
Amending claim 5 to recite “wherein in the DNT cell culture medium comprises 40-80 units/ml of gentamicin, 150-1000 IU/ml of recombinant human interleukin 2, 5-20 ng/ml of recombinant human interleukin 15, 1-5 ng/ml of recombinant human interleukin 7, 5-20 ng/ml of recombinant human interleukin 12, and 3-25 v% of autologous plasma” would obviate this part of the rejection.
Claim 5 also recites “the single-chain variable region of an antibody targeting CD19” in line 8. However, there is no mention of an anti-CD19 single-chain variable region in claim 5 prior to this limitation. Therefore, the limitation recited in line 8 lacks antecedent basis. Amending claim 5 to recite “a single-chain variable region of an antibody targeting CD19” would obviate this part of the rejection.
Claim 7 recites “the viral expression vector of step (i)” in line 1. However, claim 7 is dependent on claim 5 which does not recite “a viral expression vector.” Therefore, the limitation recited in line 1 or claim 7 lacks antecedent basis. Amending claim 7 to recite “wherein nucleotide sequence is SEQ ID NO: 16” in line 1 would obviate this part of the rejection.
Written Description
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 1-8 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 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.
The instant claims are drawn to a universal CAR-DNT cell targeting CD19, the CAR construct having a structure as shown in Formula I: L-scFv-H-TM-C-CD3
ζ
(Formula I) wherein L is none or a signal peptide sequence; scFv is a sequence of a single-chain variable region of an antibody targeting CD19, wherein the scFv comprises a VH having an amino acid sequence as shown in SEQ ID NO: 6 and a VL having an amino acid sequence as shown in SEQ ID NO: 5; H is a hinge region; TM is a transmembrane domain; C is a co-stimulatory signaling molecule; CD3
ζ
is a cytoplasmic signaling sequence derived from CD3
ζ
; and each "-" independently indicates a linking peptide or peptide bond connecting each of the above elements; a method of preparing the universal CAR-DNT cell targeting CD19; and a pharamaceutical composition comprising the universal CAR-DNT cell targeting CD19.
The Applicant has only disclosed a single species of CD19 CAR (SEQ ID NO: 14) which comprises a CD8 leader sequence encoded by SEQ ID NO: 8 and an anti-CD19 scFv of SEQ ID NO: 4 which has the formula VL-Linker-VH, wherein the VL is SEQ ID NO: 5, the linker is SEQ ID NO: 7, and the VH is SEQ ID NO: 7 (e.g. see page 22, line 28 – page 23, line 22; and 25, lines 5-19).
Independent claim 1 recites that the CAR comprises a scFv comprising a VH and a VL, wherein the VH and VL have an amino acid sequence of SEQ ID NOs: 5 and 6, respectively.
Dependent claim 2 recites that the scFv has an amino acid sequence of SEQ ID NO: 4.
Dependent claim 4 recites that the CAR construct has an amino acid sequence of SEQ ID NO: 14.
Dependent claim 5 recites that the CAR construct may or may not comprise a signal peptide sequence and does not recite any structure for the anti-CD19 scFv.
Dependent claim 7 recites that the nucleotide sequence encoding the CAR construct has an amino acid sequence of SEQ ID NO: 16.
It is noted that the VH and VL (claim 1), scFv (claim 2), CAR construct (claim 4), and nucleotide sequence encoding the CAR construct (claim 7) of the instant invention are defined broadly to be any VH and VL, scFv, CAR construct, and nucleotide sequence encoding the CAR construct with a sequence that is at least two consecutive amino acids/nucleotides of SEQ ID NOs: 6 and 5, 4, 14, or 16, respectively.
When given the broadest reasonable interpretation in light of specification, the CD19CAR-DNT cell of the instant invention is defined broadly to be any CD19CAR-DNT cell that comprises any CD19CAR that may or may not comprise a signal peptide sequence and any scFv comprising any VH and any VL, wherein the VH and VL have any amino acid sequence comprising two or more consecutive amino acids of SEQ ID NOs: 5 and 6, respectively.
It is noted that claim 1 (or any dependent claim thereof) does not indicate sufficient structure for the genus of CD19CAR-DNT cells as claimed.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or 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 genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Regarding the anti-CD19 scFv, artisans are well aware that knowledge of a given antigen (for instance CD19) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen, as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection).
Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
This applies to the instant invention which is drawn to a genus of anti-CD19 scFv which comprise as little as two consecutive amino acids from SEQ ID NOs: 6 and 5, 4, or 14. This also applies to the instant invention which is drawn to a method of preparing the CD19CAR-DNT cell by providing an expression vector containing a nucleotide sequence encoding a CAR construct that comprises an anti-CD19 scFv without any structure (claim 5) or wherein the nucleotide sequence encoding a CAR construct that comprises an anti-CD19 scFv comprises as little as two consecutive nucleotides of SEQ ID NO: 16 (claim 7).
Regarding a CAR construct with or without a signal peptide sequence, Nesmeyanova et al. 2024 (Curr. Issues Mol. Biol. 46(12), 14464-14475) teach that signal peptides are crucial for the synthesis and secretion of recombinant proteins, guiding the transport of the nascent polypeptide to the lumen of a subcellular compartment and initiating the protein secretion pathway (e.g. see page 14465, third paragraph). Nesmeyanova et al. also teach that one frequently overlooked aspect of expression vectors is the nucleotide sequence encoding the signal peptide, which plays a pivotal role in facilitating the secretion of recombinant proteins (e.g. see Abstract).
This applies to the instant invention, namely claims 5-7, which is drawn to a method of preparing the CD19CAR-DNT cell by providing an expression vector containing a nucleotide sequence encoding a CAR construct that may or may not have a signal peptide sequence or wherein the nucleotide sequence encoding a CAR construct comprises as little as two consecutive amino acid sequences from SEQ ID NO: 16.
Based on the art, a skilled artisan would reasonably expect that a nucleotide sequence encoding a CAR construct lacking a signal peptide could not be used to express the CAR on the cell membrane where its antigen-binding domain is displayed extracellularly and is able to bind CD19-expressing cells. The nucleotide sequence of claims 5-7 must comprise a signal peptide-encoding portion in order for the CD19CAR-DNT cell to be able to target CD19. Without the encoded signal peptide, the antigen-binding domain of the CD19CAR will remain in the cytosol and not be expressed on surface of the DNT cell and, in turn, the CD19CAR-DNT cell will not be able to target CD19.
As noted above, the Applicant has only disclosed a single species of CD19 CAR (SEQ ID NO: 14) which comprises a CD8 leader sequence encoded by SEQ ID NO: 8 and an anti-CD19 scFv of SEQ ID NO: 4. Such a disclosure does not serve to provide sufficient written description of the claimed (1) genus of CD19CAR-DNT cells that comprise/are encoded by as little as two consecutive amino acids/nucleotides from SEQ ID NOs: 6 and 5, 4, 14, or 16, respectively, and (2) method of preparing the CD19CAR-DNT cell by providing an expression vector containing a nucleotide sequence encoding a CAR construct that (a) that may or may not have a signal peptide sequence, (b) comprises an anti-CD19 scFv without any structure, and (c) wherein the nucleotide sequence comprises as little as two consecutive nucleotides of SEQ ID NO: 16.
Further, the disclosure does not identify any specific structural features or combination of features which give rise to the function of targeting CD19. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited CD19CAR-DNT cells or method of preparing them which gives rise to their functional activity. Ultimately, identifying a CD19CAR-DNT cell or method of preparing a CD19CAR-DNT cell simply on the basis of targeting CD19 rather than by identifying the sequence/structure, namely the CDRs and a nucleotide sequence encoding a signal peptide sequence and the CDRs, of the CD19CAR-DNT cells and the method of preparing them, respectively, in question is generally insufficient to provide written description.
Ultimately, there is insufficient written description for the breadth of (1) CD19CAR-DNT cells that comprise/are encoded by as little as two consecutive amino acids/nucleotides from SEQ ID NOs: 6 and 5, 4, 14, or 16, respectively, and (2) the method of preparing the CD19CAR-DNT cell by providing an expression vector containing a nucleotide sequence encoding a CAR construct that (a) that may or may not have a signal peptide sequence, (b) comprises an anti-CD19 scFv without any structure, and (c) wherein the nucleotide sequence comprises as little as two consecutive nucleotides of SEQ ID NO: 16. Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of CD19CAR-DNT cells or the method of preparing them encompassed by the claims at the time the instant application was filed.
Amending the claims as follows would obviate this part of the rejection:
Claim 1 to recite “wherein the scFv comprises a heavy chain variable region (VH) of having the amino acid sequence of SEQ ID NO: 6 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 5” in lines 8-10;
Claim 2 to recite “wherein the scFv has the amino acid sequence of SEQ ID NO: 4” in lines 1-2;
Claim 4 to recite “wherein the CAR construct has the amino acid sequence of SEQ ID NO: 14” in lines 1-2;
Claim 5 to recite “L is a signal peptide sequence” in line 7 and “scFv is a sequence of a single-chain variable region of an antibody targeting CD19, wherein the scFv comprises a heavy chain variable region (VH) of having the amino acid sequence of SEQ ID NO: 6 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 5” in line 8; and
Claim 7 to recite “wherein the nucleotide sequence is SEQ ID NO: 16” in line 1.
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.
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.
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.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over the 102(a)(2) reference Wu and Golubovskaya 2020 (US 20200354451 A1, has an effective filing date of 12/22/2017) in view of Lee et al. 2018 (Clin Cancer Res. 24 (2): 370–382).
Independent claim 1 is drawn to a universal CAR-DNT cell targeting CD19, wherein the universal CAR-DNT cell expresses an exogenous CAR construct, the CAR construct having a structure as shown in Formula I, L-scFv-H-TM-C-CD3𝞯 (Formula I), wherein L is none or a signal peptide sequence; scFv is a sequence of a single-chain variable region of an antibody targeting CD19, wherein the scFv comprises a heavy chain variable region (VH) having an amino acid sequence as shown in SEQ ID NO: 6 and a light chain variable region (VL) having an amino acid sequence as shown in SEQ ID NO: 5; H is a hinge region; TM is a transmembrane domain; C is a co-stimulatory signaling molecule; CD3𝞯 is a cytoplasmic signaling sequence derived from CD3𝞯; and each "-" independently indicates a linking peptide or peptide bond connecting each of the above elements.
Dependent claim 2 limits the universal CAR-DNT cell targeting CD19 to that wherein the scFv to has an amino acid sequence as shown in SEQ ID NO: 4.
Dependent claim 3 limits the universal CAR-DNT cell targeting CD19 to that wherein the TCR in the universal CAR-T cell is not knocked out.
Dependent claim 4 limits the universal CAR-DNT cell targeting CD19 to that wherein the CAR construct has an amino acid sequence as shown in SEQ ID NO: 14.
Dependent claim 5 is drawn to a method for preparing the universal CAR-DNT cell targeting CD19 comprising the steps of: (i) providing an expression vector, the expression vector containing a nucleotide sequence encoding a CAR construct as shown in Formula I; L-scFv-H-TM-C-CD3𝞯 (Formula I), wherein L is none or a signal peptide sequence; scFv is a sequence of a single-chain variable region of an antibody targeting CD19; H is a hinge region; TM is a transmembrane domain; C is a co-stimulatory signaling molecule; CD3𝞯 is a cytoplasmic signaling sequence derived from CD3𝞯; each "-" independently indicates a linking peptide or peptide bond connecting each of the above elements; and (ii) providing a DNT cell culture medium, the cell culture medium containing at least one DNT cell; transducing the expression vector of step (i) into the DNT cell, thereby obtaining the universal CAR-DNT cell targeting CD19, wherein in the DNT cell culture medium, the concentration of the gentamicin is 40-80 units/ml, the concentration of the recombinant human interleukin 2 is 150-1000 IU/ml, the concentration of the recombinant human interleukin 15 is 5-20 ng/ml, the concentration of the recombinant human interleukin 7 is 1-5 ng/ml, the concentration of the recombinant human interleukin 12 is 5-20 ng/ml, and the concentration of the autologous plasma is 3-25 v%.
Dependent claim 6 limits the method for preparing the universal CAR-DNT cell targeting CD19 to that wherein the expression vector is a viral expression vector.
Dependent claim 7 limits the method for preparing the universal CAR-DNT cell targeting CD19 to that wherein the viral expression vector of step (i) is integrated with a polynucleotide sequence as shown in SEQ ID NO: 16.
Dependent claim 8 is drawn to a pharmaceutical composition comprising:(a) the universal CAR-DNT cell targeting CD19; and (b) a pharmaceutically acceptable carrier, diluent or excipient.
Regarding claim 1, Wu and Golubovskaya teach a chimeric antigen receptor (CAR) comprising: (i) a single-chain variable fragment (scFv) comprising VH and VL, wherein scFv has an activity against a CD19 and wherein the VH has the amino acid sequence of SEQ ID NO: 16 and the VL has the amino acid sequence of SEQ ID NO: 14, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, (iv) an activating domain (e.g. see claim 4, [0054], and Table 6). It is noted that SEQ ID NOs: 14 and 16 are identical to instant SEQ ID NOs: 5 and 6, respectively. See sequence alignments below.
It is further noted that Wu and Golubovskaya also teach in claim 4 that the CAR may comprise SEQ ID NOs: 6 and 4 instead of SEQ ID NOs: 16 and 14, respectively. SEQ ID NOs. 6 and 4 are the VH and VL of the mouse anti-scFv and SEQ ID NOs: 16 and 14 are the humanized versions of SEQ ID NOs: 6 and 4, respectively (e,g, see [0053] and [0054]).
Further regarding claim 1, all of the CAR constructs taught by Wu and Golubovskaya comprise a signal peptide sequence, a hinge region, and a CD3𝞯 cytoplasmic signaling sequence (e.g. see Figure 2).
Regarding claim 6, Wu and Golubovskaya also teach the synthesis of DNA encoding the CD19 CAR which were subcloned into a third-generation lentiviral vector (e.g. see [0060]).
Regarding claims 1 and 5, CD19 CAR T cells were generated by adding the CD19 CAR-encoding lentiviral vectors to PBMC cultures that were pre-treated to induce T cell expansion (e.g. see [0061]).
Regarding claim 2, Wu and Golubovskaya teach that a CD19-CAR containing the humanized clone 11 scFv (i.e. comprising SEQ ID NOs: 16 and 14), wherein the CAR sequence is similar to SEQ ID NO: 11 except for the VL and VH (e.g. see [0055]). If the VL (SEQ ID NO: 4) and VH (SEQ ID NO: 6) of SEQ ID NO: 11 are replaced with the VL (SEQ ID NO: 14) and VH (SEQ ID NO: 16) of the humanized clone 11 scFv then the CAR comprises an scFv that is identical to instant SEQ ID NO: 4. See sequence alignment below.
Regarding claim 4, it is noted that since the modified SEQ ID NO: 11 taught by Wu and Golubovskaya comprises instant SEQ ID NO: 4 and therefore comprises at least two consecutive amino acid sequences of instant SEQ ID NO: 14. See sequence alignment below.
Regarding claim 7, Wu and Golubovskaya teach nucleic acid encoding the CAR (e.g. see claim 11, [0034], and [0060]). It is noted that the CD19 CAR construct of modified SEQ ID NO: 11 comprises multiple methionine and tryptophan residues both of which are encoded by only one nucleotide codon each, i.e. ATG and TGG, respectively. Therefore, a nucleic acid encoding modified SEQ ID NO: 11 would at least comprise several ATG and TGG codons. Thus, the nucleic acid sequence taught by Wu and Golubovskaya would comprise at least two consecutive nucleotides of SEQ ID NO: 16.
Regarding claim 8, Wu and Golubovskaya teach a pharmaceutical composition comprising the CD19 CAR T cell and a pharmaceutically acceptable carrier, diluent, or excipient which was injected into NSG mice by i.v (intravenously) (e.g. see [0077]). It is noted that a skilled artisan would understand that in order for the CD19 CAR T cells to be delivered by i.v. they would need to be suspended in a pharmaceutically acceptable carrier, diluent, or excipient, such as water or buffer.
Further regarding claim 5, Wu and Golubovskaya teach the T cell culture medium AIM V-AlbuMAX medium (Thermo Fisher) containing 10% FBS and 300 U/ml IL-2 (Thermo Fisher) (e.g. see [0061]). AIM-V medium contains gentamicin (60 units/ml), recombinant human interleukin 2 (250 IU/ml), recombinant human interleukin 15(10 ng/ml), recombinant human interleukin 7 (2 ng/ml), recombinant human interleukin 12 (10 ng/ml), and autologous plasma (20 v%) (e.g. see instant page 27, lines 2-5).
Alignment of Wu and Golubovskaya’s SEQ ID NO: 14 and instant SEQ ID NO: 5:
Query Match 100.0%; Score 563; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGGGTKVEIK 107
Alignment of Wu and Golubovskaya’s SEQ ID NO: 16 and instant SEQ ID NO: 6:
Query Match 100.0%; Score 637; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQESGPGLVKPSETLSLTCTVSGGSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQESGPGLVKPSETLSLTCTVSGGSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYN 60
Qy 61 SALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 120
Alignment of Wu and Golubovskaya’s modified SEQ ID NO: 11 and instant SEQ ID NO: 4:
Query Match 48.1%; Score 1294; DB 1; Length 245;
Best Local Similarity 100.0%;
Matches 245; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 23 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPS 82
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPS 60
Qy 83 RFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGGGTKVEIKGSTSGSGKPGSGE 142
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGGGTKVEIKGSTSGSGKPGSGE 120
Qy 143 GSTKGQVQLQESGPGLVKPSETLSLTCTVSGGSLPDYGVSWIRQPPGKGLEWIGVIWGSE 202
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSTKGQVQLQESGPGLVKPSETLSLTCTVSGGSLPDYGVSWIRQPPGKGLEWIGVIWGSE 180
Qy 203 TTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTL 262
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTL 240
Qy 263 VTVSS 267
|||||
Db 241 VTVSS 245
Alignment of Wu and Golubovskaya’s modified SEQ ID NO: 11 and instant SEQ ID NO: 14:
Query Match 70.7%; Score 1900.5; DB 1; Length 489;
Best Local Similarity 73.9%;
Matches 386; Conservative 24; Mismatches 61; Indels 51; Gaps 9;
Qy 1 MLLLVTSLLLCELPHPAFLLI----PDIQMTQSPSSLSASVGDRVTITCRASQDISKYLN 56
| | ||:||| | ||: |||||||||||||||||||||||||||||||||||
Db 1 MALPVTALLL-----PLALLLHAARPDIQMTQSPSSLSASVGDRVTITCRASQDISKYLN 55
Qy 57 WYQQKPGKAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTL 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 56 WYQQKPGKAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTL 115
Qy 117 PYTFGGGTKVEIKGSTSGSGKPGSGEGSTKGQVQLQESGPGLVKPSETLSLTCTVSGGSL 176
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 116 PYTFGGGTKVEIKGSTSGSGKPGSGEGSTKGQVQLQESGPGLVKPSETLSLTCTVSGGSL 175
Qy 177 PDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAAD 236
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 176 PDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAAD 235
Qy 237 TAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSAAAKNPDPWAKNLNEKDYIEVMYPPPYLD 296
||||||||||||||||||||||||||||||| | | | | :
Db 236 TAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRP-------------PTPAPTIA 282
Qy 297 NE----------KSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAF 346
:: : | :| :| : :: : | | ||:::
Db 283 SQPLSLRPEACRPAAGGAVHTRGLDF---------ACDIYIWAPLAG--TCGVLLLSLVI 331
Qy 347 IIFWVRSKRSRLLHSDYMNMTP-RRPGPTRKHYQPYA---PPRDFAAYRSRVKFSRSADA 402
:: | :: | |: | || | : : | : ||||||||||
Db 332 TLYCKRGRKKLL----YIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADA 387
Qy 403 PAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEA 462
|||:||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 388 PAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEA 447
Qy 463 YSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 504
||||||||||||||||||||||||||||||||||||||||||
Db 448 YSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 489
Wu and Golubovskaya do not teach that the CD19CAR-T cell is a universal CD19CAR-DNT cell (claim 1). Wu and Golubovskaya also do not teach that the TCR in the universal CD19CAR-DNT is not knocked out (claim 3).
Regarding claim 1, Lee et al. teach that DNTs are mature peripheral T lymphocytes expressing CD3–T-cell receptor (TCR) complex but not CD4, CD8, nor invariant NK T-cell markers (e.g. see paragraph spanning pages 370 and 371). They represent 1% to 3% of peripheral blood mononuclear cells (PBMC) (e.g. see paragraph spanning pages 370 and 371). It has been shown that DNTs could be expanded from peripheral blood of a small number of AML patients during chemotherapy-induced complete remission and were able to kill autologous AML cells in vitro (e.g. see paragraph spanning pages 376 and 377). Lee et al. also teach that broad, yet cancer-specific cytotoxic activity of DNTs was also seen against cell lines derived from other forms of leukemia and lymphoma (e.g. see paragraph spanning pages 376 and 377).
Further regarding claim 1, Lee et al. further teach that importantly, although DNTs were cytotoxic to CD34+ AML cells in vitro and inhibited their engraftment in PDX models, they did not affect normal stem cell engraftment and differentiation (e.g. see page 377, paragraph spanning left and right columns). Contrary to the infusion of human CD4/CD8 T cells or PBMCs, infusion of human DNTs did not cause GVHD in recipients, demonstrating that DNTs selectively target leukemic cells while sparing normal cells and tissues.
Further regarding claim 1, Lee et al. ultimately teach that given that ex vivo expanded allogeneic DNTs from healthy donors (HDs) have no observed toxicity, can target broad range of leukemia cells in a donor-unrestricted manner and are cryopreservable, these cells can potentially be used as a new “off-the-shelf” cellular therapy for treating leukemia. Further regarding claim 1 and also regarding claim 3, given their superior expansion profile, potent cytotoxic function, and lack of allo-response by endogenous TCRs, DNTs would be a good vehicle for CAR or transgenic TCR technology (e.g. see page 377, paragraph spanning left and right columns).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Wu and Golubovskaya to incorporate the teachings of Lee et al. to include that the CD19CAR-T cell is a universal CD19CAR-DNT cell and that the TCR in the universal CD19CAR-DNT is not knocked out. This is because ex vivo expanded allogeneic DNTs from HDs have the potential to be used as a new “off-the-shelf” (or universal) cellular therapy for treating leukemia and would be a good vehicle for CAR technology (Lee et al.).
Ex vivo expanded allogeneic DNTs from HDs have no observed toxicity, can target broad range of leukemia and lymphoma cells in a donor-unrestricted manner, are cryopreservable, have a superior expansion profile, have potent cytotoxic function, and lack allo-response by endogenous TCRs (no GVHD) (Lee et al.). Given these characteristics, ex vivo expanded allogeneic DNTs from HDs have the potential to be used as a new “off-the-shelf” cellular therapy for treating leukemia and would be a good vehicle for CAR technology (Lee et al.). Therefore, it would have been obvious to a skilled artisan to modify the CD19CAR-T cell taught by Wu and Golubovskaya into a universal CD19CAR-DNT cell with a reasonable expectation of success. Given Lee et al.’s teachings, a skilled artisan would reasonably expect a CD19CAR-DNT to be a new “off-the-shelf” cellular therapy with little-to-no toxicity and broad and potent cytotoxic function toward a range of cancers in a donor-unrestricted manner.
Regarding the limitation of claim 3, wherein the TCR in the universal CD19CAR-DNT is not knocked out, given Lee et al.’s teachings that the ex vivo expanded allogeneic DNTs from HDs lack allo-response by endogenous TCRs; it would be obvious to a skilled artisan to not knock out the endogenous TCR of the CD19CAR-DNT cell taught by Wu and Golubovskaya in view of Lee et al. with a reasonable expectation of success. Given that the endogenous TCR of the DNTs presents no concern for an allogenic response/GVHD, it would be unnecessary, or even tedious, for a skilled artisan to also knock out the endogenous TCR when engineering the CD19CAR-DNT.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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 1-8 are rejected on the ground of nonstatutory double patenting (NSDP) as being unpatentable over claims 1-11 of U.S. Patent No. 12,202,896 (the ‘896 Patent) in view the 102(a)(2) reference Wu and Golubovskaya 2020 (US 20200354451 A1, has an effective filing date of 12/22/2017) and Lee et al. 2018 (Clin Cancer Res. 24 (2): 370–382)
The instant claims are drawn to (1) a universal CAR-DNT cell targeting CD19, wherein the universal CAR-DNT cell expresses an exogenous CAR construct, the CAR construct having a structure as shown in Formula I, L-scFv-H-TM-C-CD3𝞯 (Formula I), wherein L is none or a signal peptide sequence; scFv is a sequence of a single-chain variable region of an antibody targeting CD19, wherein the scFv comprises a heavy chain variable region (VH) having an amino acid sequence as shown in SEQ ID NO: 6 and a light chain variable region (VL) having an amino acid sequence as shown in SEQ ID NO: 5; H is a hinge region; TM is a transmembrane domain; C is a co-stimulatory signaling molecule; CD3𝞯 is a cytoplasmic signaling sequence derived from CD3𝞯; and each "-" independently indicates a linking peptide or peptide bond connecting each of the above elements; (2) a method for preparing the universal CAR-DNT cell targeting CD19; and (3) a pharmaceutical composition comprising the universal CAR-DNT cell targeting CD19.
The claims in the ‘896 Patent are drawn to a humanized single-chain variable fragment (scFv) of CD19 comprising VH having the amino acid sequence of SEQ ID NO: 6 and VL having the amino acid sequence of SEQ ID NO: 5; a chimeric antigen receptor (CAR) fusion protein comprising from N-terminus to C-terminus: (i) the scFv of claim 1, (ii) a transmembrane domain, (iii) at least one co-stimulatory domain, and (iv) an activating domain; wherein the CAR has the amino acid sequence of SEQ ID NO: 14; an antibody; a nucleic acid molecule; a vector; a host cell expressing the CAR, a formulation; and a method for treating cancer or tumor.
It is noted that SEQ ID NOs: 5, 6, and 14 are identical to instant SEQ ID NO: 5, 6, and 14. It is further noted that the CAR construct of SEQ ID NO: 14 comprises a CD19 scFv that is identical to instant SEQ ID NO: 4. See sequence alignments below
Sequence alignment of the ‘896 Patent’s SEQ ID NO: 5 and instant SEQ ID NO: 5:
Query Match 100.0%; Score 563; DB 1; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGGGTKVEIK 107
Sequence alignment of the ‘896 Patent’s SEQ ID NO: 6 and instant SEQ ID NO: 6:
Query Match 100.0%; Score 637; DB 1; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQESGPGLVKPSETLSLTCTVSGGSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQESGPGLVKPSETLSLTCTVSGGSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYN 60
Qy 61 SALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 120
Sequence alignment of the ‘896 Patent’s SEQ ID NO: 14 and instant SEQ ID NO: 14:
Query Match 100.0%; Score 2592; DB 1; Length 489;
Best Local Similarity 100.0%;
Matches 489; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MALPVTALLLPLALLLHAARPDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MALPVTALLLPLALLLHAARPDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQK 60
Qy 61 PGKAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PGKAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFG 120
Qy 121 GGTKVEIKGSTSGSGKPGSGEGSTKGQVQLQESGPGLVKPSETLSLTCTVSGGSLPDYGV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GGTKVEIKGSTSGSGKPGSGEGSTKGQVQLQESGPGLVKPSETLSLTCTVSGGSLPDYGV 180
Qy 181 SWIRQPPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYY 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SWIRQPPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYY 240
Qy 241 CAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 CAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGA 300
Qy 301 VHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEE 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 VHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEE 360
Qy 361 DGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDP 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 DGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDP 420
Qy 421 EMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDA 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 EMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDA 480
Qy 481 LHMQALPPR 489
|||||||||
Db 481 LHMQALPPR 489
Sequence alignment of the ‘896 Patent’s SEQ ID NO: 14 and instant SEQ ID NO: 4:
Query Match 49.9%; Score 1294; DB 1; Length 245;
Best Local Similarity 100.0%;
Matches 245; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 22 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPS 81
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPS 60
Qy 82 RFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGGGTKVEIKGSTSGSGKPGSGE 141
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGGGTKVEIKGSTSGSGKPGSGE 120
Qy 142 GSTKGQVQLQESGPGLVKPSETLSLTCTVSGGSLPDYGVSWIRQPPGKGLEWIGVIWGSE 201
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSTKGQVQLQESGPGLVKPSETLSLTCTVSGGSLPDYGVSWIRQPPGKGLEWIGVIWGSE 180
Qy 202 TTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTL 261
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTL 240
Qy 262 VTVSS 266
|||||
Db 241 VTVSS 245
The claims in the ‘896 Patent differ from the instant invention by not reciting a universal CD19CAR-DNT cell (instant claim 1) or that the TCR in the universal CD19CAR-DNT is not knocked out (instant claim 3).
The teachings of Wu and Golubovskaya and Lee et al. are outlined in the 103 rejection above. It is noted that SEQ ID NOs: 5, 6, and 14 of the ‘896 Patent are identical to or comprise SEQ ID NOs: 11, 14, and 16 of Wu and Golubovskaya. See the 103 rejection above.
It would be obvious to one of ordinary skill in the art modify the claims in the ‘896 Patent to incorporate the teachings of Wu and Golubovskaya and Lee et al. to include a universal CD19CAR-DNT cell and that the TCR in the universal CD19CAR-DNT is not knocked out. This is because Wu and Golubovskaya teach a CD19CAR-T cell comprising an anti-CD19 scFv that is identical to instant SEQ ID NO: 4 and the ‘896 Patent’s SEQ ID NO: 14 and because ex vivo expanded allogeneic DNTs from HDs have the potential to be used as a new “off-the-shelf” (or universal) cellular therapy for treating leukemia and would be a good vehicle for CAR technology (Lee et al.).
Regarding claims 1-3 and 5 of the ‘896 Patent, which are drawn to an anti-CD19 scFv and an anti-CD19 antibody, given that an anti-CD19 scFv comprising an identical full length and VH and CL amino sequences has already been incorporated into a CD19CAR-T cell (Wu and Golubovskaya); it would be obvious to use the ‘896 Patent’s anti-CD19 scFv or anti-CD19 antibody in a CD19CAR construct comprising an anti-CD19 scFv with a reasonable expectation of success.
Regarding claims 4 and 6-11, which are drawn to a CD19CAR, a nucleic acid encoding the CD19CAR, a vector comprising the nucleic acid, a host cell expressing the CD19CAR, and a formulation comprising the host cell expressing the CD19CAR; it is noted that ex vivo expanded allogeneic DNTs from HDs have no observed toxicity, can target broad range of leukemia and lymphoma cells in a donor-unrestricted manner, are cryopreservable, have a superior expansion profile, have potent cytotoxic function, and lack allo-response by endogenous TCRs (no GVHD) (Lee et al.). Given these characteristics, ex vivo expanded allogeneic DNTs from HDs have the potential to be used as a new “off-the-shelf” cellular therapy for treating leukemia and would be a good vehicle for CAR technology (Lee et al.).
Therefore, it would be obvious to a skilled artisan to use the CD19CAR, nucleic acid encoding the CD19CAR, and vector comprising the nucleic acid of the ‘896 Patent and modify the host cell expressing the CD19CAR and formulation comprising the host cell expressing the CD19CAR of the ‘896 Patent in/into a universal CD19CAR-DNT cell or method for producing the universal CD19CAR-DNT cell with a reasonable expectation of success. Given Lee et al.’s teachings, a skilled artisan would reasonably expect a CD19CAR-DNT to be a new “off-the-shelf” (or universal) cellular therapy with little-to-no toxicity and broad and potent cytotoxic function toward a range of cancers in a donor-unrestricted manner.
Regarding the limitation of instant claim 3, wherein the TCR in the universal CD19CAR-DNT is not knocked out, given Lee et al.’s teachings that the ex vivo expanded allogeneic DNTs from HDs lack allo-response by endogenous TCRs; it would be obvious to a skilled artisan to not knock out the endogenous TCR of the CD19CAR-DNT cell taught by Wu and Golubovskaya in view of Lee et al. with a reasonable expectation of success. Given that the endogenous TCR of the DNTs presents no concern for an allogenic response/GVHD, it would be unnecessary, or even tedious, for a skilled artisan to also knock out the endogenous TCR when engineering the CD19CAR-DNT.
Regarding the limitation of instant claim 5 drawn to the DNT culture medium, given that Wu and Golubovskaya teach the T cell culture medium AIM V (e.g. see [0061]) which contains gentamicin (60 units/ml), recombinant human interleukin 2 (250 IU/ml), recombinant human interleukin 15(10 ng/ml), recombinant human interleukin 7 (2 ng/ml), recombinant human interleukin 12 (10 ng/ml), and autologous plasma (20 v%) (e.g. see instant page 27, lines 2-5); it would be obvious to use the AIM-V culture medium to also culture the DNT cells in a method of preparing the CD19CAR-DNT cells taught by the ‘896 Patent in view of Wu and Golubovskaya and Lee et al. with a reasonable expectation of success.
More specifically regarding claims 6 and 7 of the ‘896 Patent, which are drawn to a nucleic acid molecule encoding the CD19CAR and vector comprising the nucleic acid molecule, given that Wu and Golubovskaya also teach the synthesis of DNA encoding the CD19 CAR which were subcloned into a third-generation lentiviral vector; it would be obvious to a skilled artisan to use a viral vector to encode the CD19CAR with a reasonable expectation of success. Furthermore, specifically regarding instant claim 7, given that the CD19CAR of the ‘896 Patent is identical to the instant CD19CAR, which comprises multiple methionine and tryptophan residues both of which are encoded by only one nucleotide codon each, i.e. ATG and TGG, respectively; a nucleic acid encoding said CD19CAR would at least comprise several ATG and TGG codons. Thus, the nucleic acid and vector taught by claims 6 and 7 of the ‘896 Patent would comprise at least two consecutive nucleotides of SEQ ID NO: 16.
More specifically regarding claim 11 of the ‘896 Patent, which is drawn to a method for treating cancer or tumor comprising administering host cell comprising the CD19CAR, given that the claim uses the host cell comprising the CD19CAR, it would be obvious to a skilled artisan to modify said host cell comprising the CD19CAR into a CD19CAR-DNT cell for the reasons outlined above.
As such, the claims in the ‘896 Patent would render the instant claims obvious.
Conclusion
No claim is allowed.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641