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 .
Status of the Claims
Claims 1-15 and newly added claim 21 are currently under consideration.
Claim Rejections - 35 USC § 112(b)
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 1-15 and 21 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 is drawn to a chimeric antigen receptor (CAR) wherein the extracellular region comprises a CD22 and CD19 binding domain consisting of
CD19VL-CD22VL-CD22VH-CD19VH or CD22VL-CD19VL-CD19VH-CD22VH.
The transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim, while "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps (see MPEP § 2111.03(I and II)). The scope of the CD22 and CD19 binding domain is unclear. For example, are linkers between the VH and VL domains outside the scope as “consisting of” suggests or, alternatively, are linkers within the scope as “comprising” suggests. In addition, dependent claims 11 and 21 recite Seq ID Nos: 4 and 12 wherein there are linkers present between the VH and VL domains as “comprising” allows for. It is noted should Applicant determine linkers are excluded from the scope of claim 1 then it is unclear how the CAR or the extracellular domain of the CAR can comprise Seq ID Nos: 4 or 12 as recited in claims 11 and 21 given Seq ID Nos: 4 and 12 comprise linkers between the various domains.
Claim 4 is drawn to the transmembrane region wherein the transmembrane domain is selected from the following proteins or an amino acid sequence having 90-99% homology with a particular list of proteins. First, it is unclear if the list of proteins starting in lines 6-8 are associated with both “a transmembrane domain selected from the following proteins” (line 5) and “an amino acid sequence having 90-99% homology with the proteins” (lines 5-6) as both clauses imply a list of proteins while there is only one list. Alternatively, is the claim missing a list of proteins as there is no list following the clause “a transmembrane domain selected from the following proteins” (line 5). Second, it is unclear what is within the scope of “an amino acid sequence having 90-99% homology”. For example, is a protein with 90-99% sequence identity to the recited proteins within the scope as “an amino acid sequence” suggests. Alternatively, is a protein with 90-99% similar function, relative position, or structure comprising any amino acid sequence within the scope as the word “homology” is drawn to having the same or similar function, relative position, or structure.
Claim 5 is drawn to wherein “the hinge region is a hinge region sequence in CD8α”. It is unclear what is within the scope of the hinge region. For example, does the hinge region encompass CD8α hinge fragments (i.e., any two or more amino acids found in a CD8α hinge sequence) as “the hinge region is a hinge region sequence in” suggests or alternatively is does the hinge region comprise a CD8α hinge sequence.
Claim 7 is drawn to the costimulatory factor wherein the costimulatory factor one or more of functional signal domains obtained from one or more of the following proteins or the amino acid sequence having 90-99% homology with a particular list of proteins wherein the one or more proteins is selected from the group consisting of. First, it is unclear if the list of proteins starting in lines 5-15 are associated with both “one or more of functional signal domains obtained from one or more of the following proteins” (lines 2-3) and “the amino acid sequence having 90-99% homology with the proteins” (lines 3-4) as both clauses imply a list of proteins while there is only one list. Alternatively, is the claim missing a list of proteins as the claim language is drawn to alternatives (i.e., functional signal domains vs 90-99% homology). Second, claim 7 recites the limitation "the amino acid sequence" in lines 3-4. There is insufficient antecedent basis for this limitation in the claim. Third, it is unclear what is within the scope of “an amino acid sequence having 90-99% homology”. For example, is a protein with 90-99% sequence identity to the recited proteins within the scope as “the amino acid sequence” suggests. Alternatively, is a protein with 90-99% similar function, relative position, or structure comprising any amino acid sequence within the scope as the word “homology” is drawn to having the same or similar function, relative position, or structure. Fourth, it is unclear what protein “CDS” in line9 is naming.
Claim 8 is drawn to wherein the one or more functional signal domains is CD28 or 4-11BB or an amino acid sequence having 90-99% homology therewith. It is unclear what is within the scope of “an amino acid sequence having 90-99% homology”. For example, is a CD28 or 4-1BB protein with 90-99% sequence identity within the scope as “an amino acid sequence” suggests. Alternatively, is a CD28 or 4-1BB protein with 90-99% similar function, relative position, or structure comprising any amino acid sequence within the scope as the word “homology” is drawn to having the same or similar function, relative position, or structure.
Claim 11 is drawn to “wherein an amino acid sequence of the CAR is show in Seq ID No: 4”. It is unclear if claim 11 encompasses fragments of Seq ID No: 4 as “wherein an amino acid sequence” implies, or alternatively, excludes fragments and comprises Seq ID No: 4.
Claim 15 is drawn to the CAR of claim 10 (i.e., amino acids) comprised in an acceptable vector (i.e., DNA). It is unclear how an amino acid sequence can be comprised in a DNA vector.
Claim 21 is drawn to “wherein an amino acid sequence of the CAR is show in Seq ID No: 12”. It is unclear if claim 21 encompasses fragments of Seq ID No: 12 as “wherein an amino acid sequence” implies, or alternatively, excludes fragments and comprises Seq ID No: 12. Second, instant Seq ID No: 12 comprises 493 amino acids and appears to comprise the extracellular domain only. Therefore, it is unclear how the CAR of claim 1 which necessarily comprises a transmembrane and intracellular signal transduction regions can be set forth in Seq ID No: 12 which lacks these domains.
Applicant's arguments filed 11 December 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant has not amended nor provided arguments regarding the above 35 USC 112(b) rejections; therefore, the rejections are maintained for the reasons made of record.
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 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.
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, 4, 6-8, 10, and 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over Qin (as cited on the PTO-892 dated 05/03/2024) and WO 2017/064221 A1 (referred to herein as Ellwanger).
Qin teaches single CAR-T cells or cells expressing two different CARs present several challenges including the inefficiency of gene transfer by two vectors, associated costs for maintaining two vectors, one CAR-T cell population affecting the expansion of another CAR-T cell population, as well as other technical challenges. One strategy for overcoming these challenges is designing bispecific CAR-T cells with dual specificity in the same vector (see Qin pg. 128, 2nd col. 2nd para). Qin teaches the LoopCAR 6 structure with the following arrangement of domains: CD19VL-CD22VH-CD22VL-CD19VH (see Qin figure 4A, last structure). Qin discloses linker 1 between the CD19VL and CD22VH is GGGGS and linker 6 is GSTSGSGKPGSGEGSTKG (see Qin Sup Table 1, pg. 130, 2nd col). The CD19 and CD22 binding domains were from known clinically validated CD19 (i.e., FM63) and CD22 (i.e., m971) scFvs (see Qin pg. 128, 2nd col. 3rd para). Qin teaches the nucleic acids encoding the particular order of domains for LoopCAR6 (see Qin pg. 135, 1st col. 3rd para) with a CD8 transmembrane domain (see instant claims 4 and 5) and both 4-1 BB and CD3ζ intracellular signaling domains (see Qin figure 4; see instant claims 6-8) in a vector (i.e., lentiviral vector) and cell (i.e., T-cell) (see Qin pg. 135, 1st col. 3rd para; see instant claims 12 and 13) administered to animals(see Qin pg. 135, 2nd col. 5th para). The LoopCAR 6 structure in vitro had superior expression, IL-2 production against both CD19+/CD22- and CD19-/CD22+ ALL, and produced multiple cytokines in response to both CD19 and CD22 (see Qin para spanning pgs. 131-132). Qin teaches LoopCAR6 was effective in treating CD19+/CD22+ (i.e., HMB15) and CD19-/CD22+ (i.e., HMB29, CD19 CAR resistant) xenograft cancer models (see Qin pg. 133, 1st col., 1st para, figure 6); therefore, it necessarily follows the T-cell comprising the CD22xCD19 bispecific CAR was in a pharmaceutical composition (see instant claims 14 and 15). Qin suggests LoopCAR 6 may be effective at preventing CD19 CAR resistance and was clinical trials (see Qin pg. 133, 1st col. 1st para, 2nd col. 2nd full para). Qin does not recite wherein the order of domains is CD19VL-CD22VL-CD22VH-CD19VH.
Ellwanger discloses multivalent Fv domains wherein the centrally located diabody unit consists of a pair of two variable domains linked one after another such that these domains cannot fold intramolecularly into a functional Fv unit and instead associate with another pair of two variable domains linked one after another to form a bivalent dimer (see Ellwanger pg. 3, lines 21-24). Specifically, by linking a pair of VL domains one after another and a pair of VH domains one after another intramolecular pairing of the domains within each pair is prevented (see Ellwanger pg. 3 lines 24-27). The rigid and compact structure of the diabody unit improves manufacturability, correct folding, and stability of the binding domain (see Ellwanger pg. 3 lines 27-28). In certain embodiments the diabody unit is a single chain diabody unit defined as a first pair of variable domains connected to a second pair of variable domains by a long linker allowing intramolecular association of the first and second pairs of variable domains (see Ellwanger pg. 3 lines 31-32, figure 1 and 4, pg. 8 lines 31-32, pg. 9 lines 15-18).
A person of ordinary skill in the art would have found it obvious to swap either the CD22VH/VL or the CD19VH/VL sequences in either LoopCAR 4 or LoopCAR6 taught by Qin in order to enhance manufacturability, improve proper folding, and stability of the binding domains as taught by Ellwagner. These swaps would maintain the overall structure regarding linkers and proximal versus distal locations for the CD22 and CD19 binding domains. This is pertinent to instant claims 1, 4, 6-8, 10, and 12-15.
Applicant's arguments filed 11 December 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant argues the following:
There is no reasonable expectation of success from the experiments disclosed in Qin that the instantly claimed structure would retain binding characteristics, expression, and anti-tumor activity and the art teaches “simple swaps” of multivalent antibody architectures can affect folding, pairing, and function (see Remarks para spanning pgs. 2-3),
The instantly claimed antibody is structurally distinct from Qin’s loop constructs and specifically argues Ellwanger’s general teaching does not motivate or make obvious the rearrangements within the complex context of a bispecific loop-structure CAR (see Remarks pg. 3 middle para), and
There is a lack of motivation to combine Ellwanger’s teachings on improving manufacturability of multivalent antibody fragments to Qin’s loop-structure CAR with improved therapeutic efficacy is “speculative, not obvious” (see Remarks para spanning pgs. 3-4).
First, Applicant provides no objective evidence supporting their arguments; rather, it appears to be nothing more than attorney arguments. As set forth in the MPEP at 2145, "The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”).”
Second, Applicant suggests the instantly claimed structure is fundamentally different from any structure taught by Qin (see Remarks pg. 2 last para). This is not accurate. Both Qin and the instant application claim a CAR with a CD19 binding domain located distal to the membrane, a CD22 binding domain proximal to the membrane, and only 1 fold in the structure (see below). Therefore, the structure taught by Qin and the instantly claimed structure are largely overlapping.
Qin LoopCAR4: CD22VH-linker-CD19VL-GSTSGSGKPGSGEGSTKG-CD19VH-CD22VL- CD8 - 4-1BB - CD3ζ
Instant claim 1: CD22VL-linker-CD19VL- GSTSGSGKPGSGEGSTKG -CD19VH-CD22VH-CD8 - 4-1BB - CD3ζ
*underline denotes the CD22VH domains and italics denotes CD22VL
Figure 1.0 Qin LoopCAR4 (see Qin figure 4A, left side, 4th construct down), black box denotes the position of the CD22 VH and VL domains.
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Furthermore, Qin discloses the difference in the overall structure of TanCAR1 (i.e., CD22VH-CD22VL-CD19VL-CD19VH) and TanCAR2 (i.e., CD19VL-CD19VH-CD22VH-CD22VL) is reversing the order of binding domain relative to the membrane (see Qin pg. 128, 2nd col., Figure 3A; see also below).
Figure 2: Qin CD19 CD22 CAR (see Qin Figure 3A), black box denotes the swap of domains from TanCAR1 and TanCAR2
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Importantly, reversing the order of binding domains from TanCAR1 and TanCAR2 is not representative of the “simple swap of domains” referred to by the Examiner in the rejection above. The rejection set forth previously and above is swapping the location of a VH or VL within the same binding domain in a loop structure not tandem; thereby maintaining the distal versus proximal location of the binding domains and linkers. Qin also teaches LoopCAR4 which only requires 1 fold (see Figure 1.0 above) had superior surface expression compared to TanCAR2 which necessarily requires 2 folds (see Qin figure 3A second construct, pg. 129, 2nd col. last para, figure 3C, right panel compared to Qin figure 4C right panel). It is noted the binding domains are in the same position relative to the membrane in both TanCAR2 and LoopCAR4. This provides the ordinary artisan with motivation to maintain CD22 in the membrane proximal location and keep a reduced number of folding events. Applicant has not provided any evidence to suggest this “simple swap” which maintains the more favorable architecture (i.e., overall location of the binding domains, linker locations, and number of folds) of the structure would not maintain functional properties.
Applicant’s assertion the order of domains is distinct from what is instantly claimed is only partially accurate (see Remarks pg. 3, middle para). The positioning of the VH and VL for one binding domain deviates from Qin. However, Qin was not relied up this particular limitation (i.e., simple swap). Quinn was relied upon for a CD19 distal, CD22 proximal CAR structure. Ellwanger’s reference was relied upon for motivation to swap the domains (see above). Applicant’s Remarks are consistent with the teachings of Ellwanger:
Applicant: “It [the swap] represents a specific molecular design chosen to potentially influence dimerization tendencies, stability and avidity” (see Remarks pg. 3 middle para)
Ellwanger: “by linking a pair of variable light chain domains one after another and a pair of variable heavy chain domains one after another intramolecular pairing of the domains within each pair is prevented due to the same kind of domains…The rigid and compact structure of the diabody unit facilitates the manufacturing, correct folding of the multivalent antibody and increases the stability of the antibody” (see Ellwanger pg. 3, last full para).
Examiner disagrees with Applicant’s assertion “A person of ordinary skill in the art seeing to improve the therapeutically efficacy of a CAR would not look to Ellwanger’s teachings on diabody fragment stability with a reasonable expectation that applying its principles to Qin’s structure , would successfully yield a therapeutically effective molecule” (see Remarks para spanning pgs. 3-4). Qin regularly addresses CAR surface expression and it’s impact on function. For example,
“LoopCAR1 was constructed with the CD22 scFv (maintaining the short linker) between the VH and VL of the CD19 ScFv, a format that could only be detected at low percentages on the cell surface” (see Qin pg. 129, 2nd col.) and
“In LoopCAR4, we maintained the linker between CD19 scFv and the CD22 scFv variable chains introduced in LoopCAR3, resulting in high levels of CAR detection and superior IL2 production, compared to any of the previous formats” (see Qin pg. 130 sentence spanning cols).
Thus, Qin teaches the ordinary artisan that expression on the cell surface is one factor which effects the overall function of the CAR. Ellwanger teaches a modification that can enhance this particular feature. Thus, even if Qin’s focus is enhancing therapeutic efficacy, the ordinary artisan would readily recognize proper folding of the structure which allows the structure to function is a key component in therapeutic efficacy and Ellwanger provides strategies of enhancing stability and proper folding (see above).
Therefore, the 35 USC 103 rejection of claims 1, 4, 6-8, 10, and 12-15 is hereby maintained.
Claims 2, 3, and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Qin, Ellwanger, and in further view of Wang (see CN108715859 English translation as cited on the PTO-892 dated 05/03/2024) published 30 October 2018.
The reasons claim 1 is obvious over Qin and Ellwanger are set forth above.
Qin and Ellwanger render obvious a bispecific CD22xCD19 CAR comprising an extracellular, transmembrane, and intracellular signal transduction regions wherein the extracellular domain comprises in order either CD19VL-CD22VL-CD22VH-CD19VH or CD22VL-CD19VL-CD19VH-CD22VH; however, do not teach wherein the extracellular domain further comprises a N-terminal signal peptide.
Wang discloses a CD22scFv CAR-T cell comprising a CD22scFv and CD8α-4-1BB-CD3ζ with an identical signal sequence of the instantly claimed bispecific CAR-T cell (see Wang Seq ID No: 1, instant Seq ID Nos: 13; see sequence comparison below). Wang discloses a most preferred embodiment of the extracellular domain comprises an identical signal set forth in Seq ID NO: 4 (see Wang claim 4, pg. 2, 10th para). It is noted instant Seq ID No: 25 is disclosed as comprising a CD8α-4-1BB-CD3ζ; however, Seq ID No: 25 also comprises a CD8α hinge region given Wang discloses Seq ID No: 1 comprises a CD8α hinge region and has over 98% sequence identity to instant Seq ID No: 25(see Wang pg. 3, 10th para).
Therefore a person of ordinary skill in the art would modify the bispecific CD22xCD19 CAR taught by Qin to include a N-terminal signal peptide, specifically Wang Seq ID No: 4 given Wang discloses this is the most preferred signal peptide used in a monospecific CD22 CAR comprising a CD22 scFv and CD8α-4-1BB-CD3ζ domains wherein the CD22 scFv VH and VL are identical to the instantly claimed CD22 VH/VL and 98.4% sequence identity to the CD8α transmembrane domain, 4-1BB and CD3ζ intracellular domains (see sequence comparison below; see instant Seq ID No: 25). This is pertinent to instant claims 2 and 3. Likewise, a person of ordinary skill in the art would use/substitute the hinge region of the CD22xCD19 bispecific CAR taught by Qin for the CD8α hinge region taught by Wang given both Qin and Wang disclose a CAR comprising identical transmembrane and intracellular signaling domains. There is a reasonable expectation of success given both references teach a functional CAR comprising these domains (i.e., transmembrane and intracellular domains) and the hinge region is from the same protein as the transmembrane domain. This is pertinent to instant claim 5.
Applicant's arguments filed 11 December 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant argues incorporation of the art recognized domains into the “non-obvious bispecific CAR scaffold of claim 1” does not render claims 2, 3, and 5 obvious.
The 35 USC 103 rejection of claims 2, 3, and 5 is maintained for the reasons made of record and set forth above.
Claims 11 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Qin, Ellwanger, Wang (see CN108715859 English translation as cited on the PTO-892 dated 05/03/2024) and in further view of Rao (see CN104788573 English translation as cited on the PTO-892 dated 05/03/2024) published 30 October 2018.
The reasons claims 1 and 10 are rendered obvious over Qin and Ellwanger are set forth above.
Instant claims 11 and 21 are drawn to wherein the instantly claimed bispecific CD22xCD19 CAR comprises either Seq ID Nos: 4 or 12. It is noted instant Seq ID No: 12 is found within instant Seq ID No: 4 (see sequence comparison below). It is noted instant Seq ID No: 4 and 12 comprise the following order of domains: CD22VL-CD19VL-CD19VH-CD22VH-CD8α-4-1BB-CD3ζ (see specification pg. 17 para [0073], pg. 18 para [0081]).
Qin discloses the LoopCAR 4 construct which places the CD19 scFv between the CD22 variable chains wherein CD19 is distal and CD22 is proximal to the membrane fused to a CD8, 4-1BB, and CD3ζ domains had the 2nd highest surface expression of all ten constructs (Qin pg. 130 para spanning cols. 1-2, figure 4A).
Comparison of the Qin LoopCAR4 structure and Instant Seq ID No: 4 and 12
Qin LoopCAR4: CD22VH-linker-CD19VL-linker-CD19VH-CD22VL- CD8 - 4-1BB - CD3ζ
Instant Seq ID No: 4 and 12: CD22VL-linker-CD19VL-linker-CD19VH-CD22VH- CD8 - 4-1BB - CD3ζ
*underline denotes the CD22VH domains and italics denotes CD22VL
Figure 1.0 Qin LoopCAR4 (see Qin figure 4A, left side, 4th construct down), black box denotes the position of the CD22 VH and VL domains.
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Qin suggests a membrane proximal CD22 binding domain may be optimal in loop structure (see Qin pg. 130, 2nd col). The preclinical development of a CD22 CAR, with high affinity and therapeutic efficacy as a toxin conjugate was inactive, and Qin suggests this was potentially due to its membrane distal location in contrast to the CD22 scFv with lower affinity and membrane proximal binding which was validated in a clinical trial (see Qin pg. 133, 2nd col. last para). The LoopCAR4 construct has both in vitro and in vivo efficacy (see Qin Supplemental Table 1). Qin also teaches the linker connecting the CD19 and CD22 binding domains of the more potent LoopCAR 6 construct was shorter than that of LoopCAR4 which dramatically improved both LoopCAR 6 detection and IL-2 production against both CD19+/CD22- and CD19-/CD22+ ALL (see Qin pg. 130, 2nd col. Figure 4B and 4D).
Therefore, a person of ordinary skill in the art would modify the LoopCAR 4 construct taught by Qin by swapping the CD22VH and VL domains of LoopCAR 4 given Ellwanger teaches consecutive VH or VL domains enhances manufacturability, improves proper folding, and stability of the binding domains. This would maintain the proximal/distal location of each binding domain. Furthermore, a person of ordinary skill in the art would substitute linker 2 in LoopCAR4 for linker 1 shown in LoopCAR 6 given Qin teaches the shorter linker resulted in dramatic improvement in CAR detection and IL-2 production. This would result in the following construct:
LoopCAR 4: CD22VH-linker 2-CD19VL-linker 6-CD19VH-linker 2-CD22VL- CD8-4-1BB-CD3ζ
LoopCAR 6: CD19VL-linker 1-CD22VH-linker 6-CD22VL-linker 1-CD19VH- CD8-4-1BB-CD3ζ
End Construct: CD22VL-linker 1-CD19VL-linker 6-CD19VH-linker 1-CD22VH- CD8-4-1BB-CD3ζ
*underline denotes the CD22VH domains and italics denotes CD22VL domains to be swapped as taught by Ellwanger
* bold denotes the linker to be substituted and bold underline denotes the linker to be substituted with
Qin teaches the L1 linker is GGGGS while L2 is GGGGSGGGGS (see Qin supplemental Table 1).
Wang discloses a therapeutically effective CD22scFv CAR-T cell comprising a CD22scFv and CD8α-4-1BB-CD3ζ set forth in Seq ID No: 1 which was able to increase the overall survival of in a Burkitt lymphoma model (i.e., Namalwa cells in NOD/SCID mice) (see Wang Seq ID No: 1, pg. 10, #8).
Rao discloses a CD19scFv CAR-T cell comprising a CD19scFv and CD8α-4-1BB-CD3ζ set forth in Seq ID No: 1 which was able to effectively eliminate CD19+ Nalm-6 cells in vitro (see Rao Seq ID No: 1). It is noted Rao also discloses using an identical signal peptide as instant claims 2 and 3 (see Rao Seq ID No: 7, pg. 2, 7th para, pg. 6 example 7, figure 8).
It is noted the signal peptide disclosed in the instant application, Wang, and Rao are identical and CD8-4-1BB-CD3ζ region disclosed in Wang and Rao are identical and have over 98% sequence identity (i.e., instant Seq ID No: 25 comprises a single cysteine insertion) to the same region in the instant application (see instant Seq ID No: 25).
Therefore a person of ordinary skill in the art would have substituted the FM63 CD19 antigen binding domain taught by Qin for the humanized CD19 antigen binding domain taught by Rao given these are art recognized equivalents for the same purpose (i.e., CD19 antigen binding domains) and Rao discloses the CD19 binding domain is humanized and therefore more suitable for human therapeutics. Likewise, a person of ordinary skill in the art would have substituted the m971 CD22 binding domain taught by Qin for the CD22 antigen binding domain taught by Wang given these are art recognized equivalents for the same purpose (i.e., CD22 antigen binding domains). In addition, Rao and Wang disclose identical sequences for the hinge, transmembrane, and intracellular domains which are named/used by Qin; therefore, a person of ordinary skill in the art would use the hinge, transmembrane, and intracellular domain sequences taught by Rao and Wang in a bispecific CD22xCD19 CAR given these are the domains Qin uses. As previously stated, a person of ordinary skill in the art would have substituted the L2 linker of LoopCAR4 (i.e., GGGGSGGGGS) for the L1 linker of LoopCAR 6 (i.e., GGGGS) given the dramatic improvement in surface detection and IL-2 production from the shorter linker as taught by Qin. This is pertinent to instant claims 11 and 21 (see Sequence Comparison below).
Regarding claim 9, both Wang and Rao disclose nucleotide sequences encoding either the CD22 or CD19 CAR. Upon rearrangement of the domains made obvious by Qin and Ellwanger the resulting nucleotide sequence is identical to the instantly claimed Seq ID No. 8.
Applicant's arguments filed 11 December 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant argues examiner uses hindsight reconstruction and there is no motivation in the cited art to make this precise combination of elements (see Remarks para spanning pgs. 4-5).
First, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Second, as stated above Qin teaches a CD19 (distal) CD22 (proximal) CAR and renders obvious substituting linker 2 for linker 1 (see above). Ellwanger renders obvious the CD22 VL- CD19 VL-CD19 VH- CD22 VH (see below).
LoopCAR 4: CD22VH-linker 2-CD19VL-linker 6-CD19VH-linker 2-CD22VL- CD8-4-1BB-CD3ζ
End Construct: CD22VL-linker 1-CD19VL-linker 6-CD19VH-linker 1-CD22VH- CD8-4-1BB-CD3ζ
Rao and Wang render obvious the particular sequences the ordinary artisan would choose given Rao, Wang and Qin all teach identical regions beyond the antigen binding domains. Rao and Wang each teach either a CD22 CAR or a CD19 CAR with advantages (see above); thereby, arriving at the instantly claimed invention.
The 35 USC 103 rejection of claims 11 and 21 is maintained for the reasons made of record and set forth above.
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 1-15 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 6, 9, and 11 of U.S. Patent No. 11,497,771 B2 (referred to herein as ‘771 patent) in view of Qin, Ellwanger and Wang.
Claims 1-8, 10-15, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, and 6 of U.S. Patent No. 11,547,728 B2 (referred to herein as ‘728 patent) in view of Qin, Ellwagner, and Wang.
Claims 1-15 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 10 of copending Application No. 18/056,616 (referred to herein as ‘616 application) in view of Qin, Ellwagner, and Wang.
Applicant's arguments filed 11 December 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant has not amended nor provided arguments regarding the above non-statutory double patenting rejections; therefore, the rejections are maintained for the reasons made of record.
Sequence Comparison
Instant Seq ID No: 13 (Qy) vs Wang Seq ID No: 1 (Db)
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246
532
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Greyscale
Instant Seq ID No: 25 (i.e., hinge, transmembrane, and intracellular domains) (Qy) vs Wang Seq ID No: 1 (Db)
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368
558
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Greyscale
Instant Seq ID No: 24 (i.e., CD22 scFv) (Qy) vs Wang Seq ID No: 1 (Db)
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423
543
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Greyscale
Instant Seq ID No: 23 (i.e., CD19 scFv) (Qy) vs Rao Seq ID No: 3 (Db)
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330
506
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Greyscale
Sequence comparison pertinent to instant claims 11 and 21 (see above)
It is noted Wang Seq ID No: 1 and Rao Seq ID No: 1 below show the antigen binding domains as seen directly above in sequence comparisons to instant Seq ID Nos: 23 (Rao Seq ID No: 3) and 24 (Wang Seq ID No: 1) as well as the hinge, transmembrane, and intracellular domains (hinge starts at position 276 and 269 in Wang and Rao, respectively). Qin linker 1 is GGGS and Linker 6 is GSTSGSGKPGSGEGSTKG (see Qin supplemental Table 1).
Instant Seq ID No: 4 DIELTQSPSSLAVSVGEKVTMSCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTR
Wang Seq ID No: 1 DIELTQSPSSLAVSVGEKVTMSCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTR
Rao Seq ID No: 1
Instant Seq ID No: 4 ESGVPDRFTGSGSGTDFTLTVSSVKAEDLAVYYCQQSYSYPFTFGSGTKLEIKRGGGGSDIVL
Wang Seq ID No: 1 ESGVPDRFTGSGSGTDFTLTVSSVKAEDLAVYYCQQSYSYPFTFGSGTKLEIKR
Rao Seq ID No: 1 DIVL
Qin LoopCAR 6 L1 GGGGS
Instant Seq ID No: 4 TQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRNSGVPDRFTG
Wang Seq ID No: 1
Rao Seq ID No: 1 TQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRNSGVPDRFTG
Instant Seq ID No: 4 SGSGTDFTLTITNVQSKDLADYFCQQYNRYPYTSGGGTKLEIKRGSTSGSGKPGSGEGSTKG
Wang Seq ID No: 1
Rao Seq ID No: 1 SGSGTDFTLTITNVQSKDLADYFCQQYNRYPYTSGGGTKLEIKR
Qin LoopCAR L6 4 and 6 GSTSGSGKPGSGEGSTKG
Instant Seq ID No: 4 QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGDGDTN
Wang Seq ID No: 1
Rao Seq ID No: 1 QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGDGDTN
Instant Seq ID No: 4 YNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYFCARKTISSVVDFYFDYWGQGTTLTV
Wang Seq ID No: 1
Rao Seq ID No: 1 YNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYFCARKTISSVVDFYFDYWGQGTTLTV
Instant Seq ID No: 4 SSGGGGSQVKLQQSGPELVKPGASVKISCKASGYDFSISWMNWVRQRPGQGLEWIGRIYP
Wang Seq ID No: 1 QVKLQQSGPELVKPGASVKISCKASGYDFSISWMNWVRQRPGQGLEWIGRIYP
Rao Seq ID No: 1 SS
Qin LoopCAR 6 L1 GGGGS
Instant Seq ID No: 4 GDGDSNYNGKFEGKATLTADKSSSTAYMQLSGLTSVDSAVYFCARTTTMIALYAMDYWG
Wang Seq ID No: 1 GDGDSNYNGKFEGKATLTADKSSSTAYMQLSGLTSVDSAVYFCARTTTMIALYAMDYWG
Rao Seq ID No: 1
Instant Seq ID No: 4 QGTTVTVSSEFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLA
Wang Seq ID No: 1 QGTTVTVSSEFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLA
Rao Seq ID No: 1 EFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLA
Instant Seq ID No: 4 GTCGVLLLSLVITLYKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSA
Wang Seq ID No: 1 GTCGVLLLSLVITLYKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSA
Rao Seq ID No: 1 GTCGVLLLSLVITLYKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSA
Instant Seq ID No: 4 DAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMA
Wang Seq ID No: 1 DAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMA
Rao Seq ID No: 1 DAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMA
Instant Seq ID No: 4 EAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
Wang Seq ID No: 1 EAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
Rao Seq ID No: 1 EAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(Qy) is instant Seq ID No: 23 compared to the ‘728 patent Seq ID No: 1
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425
540
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Instant Seq ID No: 4 (Qy) vs Instant Seq ID No: 12 (Db)
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788
638
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Greyscale
Conclusion
No claim allowed.
THIS ACTION IS MADE FINAL. 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.
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/H.A.P./Examiner, Art Unit 1644 /AMY E JUEDES/Primary Examiner, Art Unit 1644