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 .
Priority
This application is a U.S. national phase of International Application No.
PCT/CN2021/109867, filed on 07/30/2021. This application claims priority to PEOPLE'S REPUBLIC OF CHINA Application No. CN202010760953.3, filed 07/31/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
The Amendment, filed on 12/16/2025, is acknowledged in which: claims 8-9 and 12 are canceled; claim 6 is currently amended; claims 2-5, 10-11, and 14-17 were previously presented; claims 1 and 7 are original; and claims 18-20 are new.
Claims 1-7, 10-11, and 13-20 are pending in the instant application and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action dated 09/16/2025,
The specification was objected to for a tradename or mark used in commerce without an appropriate symbol. Applicant’s submission of an amendment to the specification with appropriate corrections has overcome the objections and the objections are withdrawn.
Claim 6 was objected to for a minor informality in the text. Applicant’s amendment to the claim has overcome the objection and the objection is withdrawn.
All previous rejections regarding claim 12 are rendered moot in view of claim cancellation.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims.
Maintained/Modified Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 1 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2008/079246 A2 (herein Xu) and Wu (Protein Eng. 2001;14(12):1025-1033).
Xu teaches a monoclonal anti-CD44 antibody (1A9.A6.B9) with VH (SEQ ID NO:11) and VL (SEQ ID NO:15) amino acid sequences that are identical to those within the instant claimed scFv (see amino acid alignment below) with corresponding nucleic acid sequences. Xu further teaches the antibody as a single-chain antibody (scFv) in which VH and VL are paired via synthetic linker that enables them to be made as a single protein chain (page 7, lines 25-27).
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Xu does not teach the synthetic linker disclosed in the instant claim amino acid sequence (highlighted above).
Wu teaches design and construction of an anti-CD20 scFv by fusing long an flexible joint between VL and VH domains using synthetic linker “GS18” with peptide sequence identical to the linker used in SEQ ID NO:1 (highlighted above) (page 1026, column 1, ‘Design and construction of anti-CD20 scFv-Fc’).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the VH and VL domains for a known anti-CD44 antibody and antigen binding fragments (i.e. scFv) as taught by Xu can combined/linked with any known scFv synthetic linker according to known methods like the GS18 sequence as taught by Wu to predictably arrive at the instantly claimed anti-CD44 scFv encoded by SEQ ID NO:1. This conclusion of obviousness is supported by KSR (A) Combining prior art elements according to known methods to yield predictable results. See MPEP 2143.
(I) Response to Arguments:
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant states:
“…Xu only discloses the VH/VL sequences of an anti-CD44 antibody, focusing on the binding characteristics of the antibody itself. It does not mention the scFv format, let alone suggest its use in CAR-T cells. Wu, on the other hand, only discloses the application of the GS18 linker in an anti-CD20 scFv, targeting the CD20 antigen, and is unrelated to the CD44 target or the CAR-T field. Their technical contexts and targets are entirely independent, with no hint suggesting their combination. The present application uses an anti-CD44 scFv in CAR-T cells, solving the problem of insufficient targeting of CD44- positive tumors by existing CAR-T therapies, which constitutes a non-obvious improvement..” (Remarks, pg 6, ¶ 6)
In response to applicant’s argument regarding the construction of scFv, Xu teaches embodiments of their disclosed anti-CD44 antibody to can be used in scFv formats by using methods known in the art (VH/VL domains fused via synthetic linker) (pg 7, lines 25-28). While, Xu does not explicitly teach a full scFv sequence, the test for obviousness not require that the claimed invention must be expressly suggested in any one or all of the references (i.e. the references need not disclose an anti-CD44 scFv to be relevant as prior art). Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art (addressed in the rejection of record and reiterated briefly in the response below). See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Briefly, Xu teaches VH/VL sequences that share identity to the instant VH/VL sequences and teaches the feasibility of using said sequences in a single chain format via flexible linker fusion. Wu teaches a suitable flexible linker (GS18) for scFv construction. Therefore, it would be obvious to a skilled artisan that combining known VH/VL sequences as taught by Xu with a known functional scFv linker as taught by Wu would have a reasonable expectation of success in creating a functional anti-CD44 scFv with identity to the sequence recited in the instant claim.
In response to applicant's argument that the references are “technical contexts and targets are entirely independent,” it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, both references speak to antibody/scFv construction, which a skilled artisan would recognize as reasonably pertinent to the inventor’s endeavor of obtaining and/or generating an scFv specific for CD44.
In response to applicant's argument that the references fail to show certain features of the invention (“an anti-CD44 scFv in CAR T-cell”), it is noted that the features upon which applicant relies (i.e., use in CAR-T cells) are not recited in these rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Claims 2 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Xu and Wu as applied to claim 1 above, and further in view of US 7,169,894 B2 (herein Martin) and Gould (Front Bioeng Biotechnol. 2014;2:41).
The combined teachings of Xu and Wu teach the anti-CD44 scFv of claim 1 as discussed above.
As discussed above in the rejection of claim 1, the combination of Xu and Wu render obvious the amino acid sequence of instant SEQ ID NO: 1, which is encoded by the nucleic acid sequence of instant SEQ ID NO: 2. Xu further teaches VH/VL nucleic acid sequences (SEQ ID NO:12 and 16, respectively) identical to VH/VL of SEQ ID NO:2 (claim 11).
While Xu and Wu do not disclose the linker nucleic acid sequence (instant SEQ ID NO:2 NA bases 364-417), reverse translation between amino acid sequences and the nucleic acids that encode them was routine in the art prior to the effective filing date of the claimed invention.
Martin discusses processes through which polynucleotides are synthesized from a specific peptide or protein that they encode both through traditional techniques and via processes where sequence analysis of the peptide is not required (abstract; column 3, lines 5-17). Martin teaches that reverse translation is the step of informational coupling of individual amino acids to their corresponding codons. Natural codons are trinucleotides and the three-nucleotide sequences of a codon specifies, or encodes, a specific amino acid (column 9, lines 29-33; Figure 1). There are 20 genetic code-encoded amino acids with 61 amino acid-encoding codons in the natural genetic code (column 18, lines 4-7; Figure 1). Martin teaches that synthesis of an encoding polynucleotide, including RNA or DNA, that encodes a specific peptide or protein conventionally involves purifying a peptide or protein and sequencing it using an automated amino acid sequencing machine. Following sequencing, the identity and order of the amino acids are read and an oligonucleotide is synthesized using a second instrument, an oligonucleotide synthesizer. From the prepared oligo, the full-length polynucleotide can be cloned and the protein can be produced (column 3, lines 5-17).
Gould teaches that advances in DNA synthesis have enabled the construction of artificial genes and freedom in de novo design of synthetic constructs. To aid this goal, a large number of software tools of variable sophistication have been implemented enabling the design of synthetic genes for sequence optimization based on rationally designed properties. Gould teaches that years recent to the publication had seen the emergence of sequence design tools that aim to evolve sequences toward combinations of objectives. Gould provides a review of the approaches that different tools have adopted to redesign genes and optimize desired coding features and discusses their strengths and limitations (abstract). Gould provides a review of the most important objectives in synthetic gene design towards optimized expression as well as a review of 11 gene design tools that were available at the time of publication that incorporate the aforementioned objectives (page 1, right column, paragraph 3; page 4, table 1). The gene design tools disclosed can be used to translate and optimize DNA sequences without altering the chain of amino acids (page 4, left column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have used the amino acid sequences disclosed by the combination of nucleotide sequences as taught by Xu and the amino acid linker Wu to arrive at the instantly claimed nucleic acids using reverse translation that was known and routine in the art as disclosed by Martin and Gould to generate sequences for the disclosed VH/VL linker. An ordinarily skilled artisan would have been able to pursue the known potential solutions with a reasonable expectation that the resulting nucleic acid would encode the amino acid sequence that it was reverse translated from, specifically the anti-CD44 scFv by the combination of the applied references.
(I) Response to Arguments:
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant states:
“Martin and Gould only teach the general principles and tools of reverse translation but do not teach how to apply them to the specific amino acid sequence of the present application, which is purportedly derived from the combination of Xu and Wu. (Remarks, pg 7, ¶ 1)
In response to applicant’s argument regarding the combination of the teachings of Martin and Gould with Xu and Wu, the test for obviousness not require that the claimed invention must be expressly suggested in any one or all of the references (i.e. the references need not disclose an anti-CD44 scFv to be relevant as prior art). Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art (addressed in the rejection of record and reiterated briefly in the response below). See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Briefly, the combined teachings of Xu and Wu teach a sequences that when combined obviate the recited instant amino acid sequence. Xu further teaches identical nucleotide sequences for VH/VL sequences (i.e. within instant SEQ ID NO: 2). While Wu teaches amino acids for the linker sequence and discloses the use of constructs (i.e. nucleic acids), Wu does not explicitly teach the corresponding nucleotides. Martin and Gould teach reverse translation was known and routine in the art at the time of filing (i.e. finite number of codons specific for amino acids as taught by Martin and with optimization tools as taught by Gould). When there is a design need (i.e. molecule cloning to incorporate a protein into a cell) or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 550 U.S. at 421, 82 USPQ2d at 1397). Therefore, a skilled artisan would have a reasonable expectation of success generating the remaining residues representing a GS18 linker as taught by Wu and generating a full scFv nucleotide sequence with identity to SEQ ID NO:2, because a skilled artisan would recognize there a finite number of nucleic acid sequences that correspond to said amino acid sequence known and commonly used in the art as taught by Martin and Gould.
Applicant states:
The scFv encoded by SEQ ID NO. 2 of this application can be stably expressed in CAR-T cells (confirmed by flow cytometry detection of CAR protein expression in Embodiment 2) and efficiently binds CD44-positive tumor cells (verified by killing assay in Embodiment 3), proving that this nucleic acid sequence is a specifically designed, functionally validated product, not a simple product of reverse translation. (Remarks, pg 7, ¶ 1)
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that these features upon which applicant relies (e.g. stable expression in CAR-T cells and use in killing assays) are not recited in these rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant states:
“The Xu and Wu documents cannot be combined to obtain the amino acid sequence (SEQ ID NO. 1) of the scFv of this application. Since "reverse translation" presupposes a specific target amino acid sequence, the Examiner's logic chain of "Xu+ Wu+ routine reverse translation" is fundamentally flawed.” (Remarks, pg 7, ¶ 1)
Applicant’s argument regarding the combination of Xu and Wu to obtain SEQ ID NO:1 is addressed above (see section 5(I)(a)). Examiner maintains the combination of Xu and Wu obviate SEQ ID NO:1, and therefore it would be obvious that a skilled examiner would have a reasonable expectation of reverse translating said sequence to the recited nucleic acid sequence as addressed above (see section 6(I)(a)).
Claims 1 and 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0247428 A1 (herein Bondanza) in view of Xu (cited above), and Wu (cited above).
Bondanza teaches chimeric antigen receptor (CAR) amino acid sequences encoding for CD44v6-CAR.28z, comprising an anti-CD44 scFv antigen binding domain fused (i.e. sequentially linked) to CD28 transmembrane domain (TMD), CD28 costimulatory domain, and CD3ζ intracellular domain (Figure 9).
Bondanza does not teach an amino acid sequence for an anti-CD44 scFv according to instant SEQ ID NO:1.
The combined teachings of Xu and Wu teach SEQ ID NO:1 as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the anti-CD44 scFv antigen binding domain within a CAR (i.e. fusion protein) as taught by Bondanza can be substituted for the scFv encoded by the amino acid sequence according to the combined teachings of Xu and Wu with a reasonable expectation of success because both scFv sequences specifically target CD44.
(I) Response to Arguments:
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant states:
“Bondanza implies conventional CAR designs but does not involve the IL7Rα domain.” (Remarks, pg 7, ¶ 2)
In response to applicant’s argument, an IL7Rα domain is not recited in these rejected claims and therefore is not relevant to the claims in question (See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993)).
Applicant states:
“There is no technical motivation supporting their [Bondanza, Xu and Wu] combination.” (Remarks, pg 7, ¶ 2)
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation (TSM) to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). However, it is just one of a number of valid rationales for doing so (see MPEP 2141(III)). In this case, it would be obvious to one of ordinary skill simply substituting an anti-CD44 scFv within a known CAR as taught by Bondanza for the anti-CD44 as taught by the combined teachings of Xu and Wu would predictably produce the same effects a CD44-specific CAR with a reasonable expectation of success.
Applicant states:
“Further, the CAR framework of this application (e.g., the fusion protein of Claim 3) needed to solve problems such as: spatial compatibility between the scFv and the transmembrane domain (e.g., CD28): ensuring the scFv efficiently recognizes the CD44 antigen without interfering with the transmembrane domain's signal transmission; and synergistic activation of the intracellular signaling domain (e.g., CD3~): requiring verification that binding of the anti-CD44 scFv to the antigen can effectively trigger T cell activation signals (killing assays in Embodiment 3 confirm a killing rate of 86.76%), which cannot be achieved by a "simple substitution" and requires inventive optimization. (Remarks, pg 7, ¶ 2)
Regarding CD44 binding activity, Xu teaches antibody VH/VL sequences with binding to CD44. Xu teaches the feasibility of generating an scFv using said VH/VL sequences and methods well known in the art, implying a reasonable expectation of maintaining CD44 affinity. In regard to functional activity of the fusion construct, as currently written the functional activity of the fusion protein is only drawn to CD44 binding activity, the remaining features the applicant relies on (signal transduction/T cell activation/and cytotoxicity) are features are not recited in the instant claims and therefore are not relevant to the claims in question (See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993)). However, Bondanza teaches that a CAR comprising a CD44 scFv is sufficient to enable CAR-T activation (Examples 4-6).
The office maintains the reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention (i.e. substituting an anti-CD44 scFv). See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016). Moreover, conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019).
Claims 5-7, 10, 17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Xu and Wu as applied to claim 1 above, and further in view of WO 2018/165228 A1 (herein Adusumilli).
The combined teachings of Xu and Wu teach claim 1 as discussed above.
Xu and Wu do not teach an expression vector comprising a first nucleic acid comprising a CD44 scFv antigen binding domain according to claim 1 (e.g. within a CAR sequence; fused to TMD and intracellular signaling domains) linked via IRES or 2A peptide to a second nucleic acid encoding an intracellular signaling molecule (i.e. multicistronic), nor transfection into T cells for CAR-T based pharmaceutical composition.
Adusumilli teaches that while immunotherapy (i.e. antibody therapy and cell-based therapies) have provided new modalities for cancer and infectious disease treatment, many malignant and/or infected cells can adapt to generate an immunosuppressive microenvironment that protects these harmful cells from immune recognition and elimination (¶ [0007]). These immunosuppressive microenvironments often must be overcome for effective treatment. Adusumillli teaches multicistronic vectors (nucleotide sequence elements engineered into an SFG γ-retroviral vector; ¶ [00370]), which encodes for a tumor antigen targeting CAR (MSLN-CAR, comprising an MSLN scFv antigen binding domain, CD28 TMD and CD3ζ intracellular signaling domain) where after the intracellular signaling element the sequence is fused to additional elements via 2A peptides including a TIM-3 scFv as an immune checkpoint inhibitor (i.e. prevents functional impairment of T cells inherent cancers and pathogenic infections; ¶ [0005]-[0006]) (Figure 1 - shown below). Adusumilli further teaches that the cancer antigen to be bound by the CAR can be chosen based on the cancer type and that it is generally understood that any cancer antigen that is accessible for CAR binding including CD44 and CD133 would be a suitable target antigens in place of MSLN (¶ [00240]-[00242]). Adusumilli teaches transfection of this vector into peripheral blood mononuclear cells (PBMCs) comprising T cells via retroviral particles for expression of the fusion protein (¶ [00372]). Adusumilli further teaches CAR-T cell populations expressing said vector within pharmaceutical composition for tumor treatment (¶ [00319] and [00379]).
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It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to utilize an anti-CD44 scFv as taught by the combined teachings of Xu and Wu within a chimeric antigen receptor construct (e.g. fused with TMD, intracellular signaling domain, 2A peptide, and TIM-3 scFv) to be expressed in T cells as a pharmaceutical composition (i.e. implied active ingredient) for the treatment of cancer as taught by Adusumilli because Adusumilli teaches that CARs that utilize cancer antigens (e.g. CD44) to stimulate T cell activation with additional elements to overcome immunosuppressive cancers can directly improve immunotherapeutic response.
(I) Response to Arguments:
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant states:
“Xu only relates to full-length anti-CD44 antibodies, and does not involve the split design
of the CAR vector expression cassette nor the connection mode via IRES/2A peptides. The
expression cassette in Adusumilli is directed to the MSLN target (not CD44), and its connection logic is CAR+2A+immune checkpoint inhibitor, without involving the dedicated connection design between the antigen-binding molecule and the intracellular signaling molecule. Wu does not involve the construction of any CAR vector and provides no relevant technical inspiration. A person skilled in the art would have no motivation to deduce the expression vector defined in Claim 5 of the present application from the cited references. Therefore, Claim 5 of the present application possesses patentability.” (Remarks, pg 8, ¶ 2)
In response to applicant’s argument that there is ‘no motivation (for combination)’, the test for obviousness does not require the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). The office maintains "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
Moreover, the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction "in light of the specification as it would be interpreted by one of ordinary skill in the art." In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827, 1830] (Fed. Cir. 2004). In regards to ‘intracellular signaling’ activity compared to ‘immune checkpoint inhibitor’ activity of an anti-TIM3 scFv as taught by Adusumilli, words are given their plain meaning unless such meaning is inconsistent with the specification - In re Morris, 127 F.3d 1048, 1054, 44 USPQ2d 1023, 1028 (Fed. Cir. 1997) (the USPTO looks to the ordinary use of the claim terms taking into account definitions or other "enlightenment" contained in the written description). The specification discloses embodiments with T2A separating CD3 domain (intracellular portion of the first nucleic acid molecule encoding the antigen-binding CAR/molecule) and an anti-TIM3 scFv (SEQ ID NOs: 6-8), therefore it would be reasonable to interpret and an anti-TIM3 scFv within scope of the “second nucleic acid fragment” as recited in the instant claim, regardless of functional activity.
In the rejection of record, all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; B/E Aerospace, Inc. v. C&D Zodiac, Inc., 962 F.3d 1373, 1379, 2020 USPQ2d 10706 (Fed. Cir. 2020); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atl. & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950).
In summary, Adusumilli teaches a multicistronic vector, which encodes for a CAR (MSLN-CAR, comprising an antigen binding scFv) where after the intracellular signaling element the sequence is fused to additional elements via 2A peptides including an TIM-3 scFv (i.e. within scope of broadest reasonable interpretation of the second nucleic acid fragment discussed above). Adusumilli teaches the suitability of other antigen targets in place of the MSLN scFv based on the cancer type (e.g. CD44). Therefore, it would be obvious to a skilled artisan to modify the multicistronic vector as taught by Adusumilli with an anti-CD44 scFv as taught by the combined teachings of Xu and Wu as a immunotherapeutic for CD44-expressing cancers. As such, subsequent arguments regarding the combination of these references (i.e. as referenced for subsequent claims 6-7, 10, 19 - Remarks, pg 8, ¶ 3 and 5; pg 9, ¶ 4) are considered unpersuasive.
Applicant states:
“Although Adusumilli employs T cells, it does not optimize transfection conditions for the CD44 target, nor does it verify the compatibility between T cells and CD44-targeted CARs.” (Remarks, pg 8, ¶ 4)
As referenced in section 7(I)(c), the office maintains the reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention (i.e. substituting an anti-CD44 scFv as discussed above). See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016). Moreover, conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019).
Applicant states:
“The prior art provides no inspiration for the rationality of selecting T cells as host cells for the treatment of CD44-positive tumors.” (Remarks, pg 8, ¶ 4)
As discussed in the rejection of record, Adusumilli teaches cell-based cancer therapies using immune cells such as T cells modified to target tumor antigens (e.g. CD44 - ¶ [00242]), have limitations for effectiveness in part due to tumor-induced immunosuppression (¶ [0004] and [0007]). Therefore a skilled artisan would recognize the benefit of using a multicistronic vector comprising a CD44-expressing cancer targeting CAR and an immune checkpoint inhibitor to overcome an immunosuppressive signal as taught by the combined teachings of Adusumilli, Xu, and Wu within T cells.
Applicant states:
“The fusion protein as defined in Claim 3 further comprises an anti-TIM3 single-chain antibody linked to the intracellular signaling domain via a T2A peptide…The TIM3 scFv in Adusumilli is tandemly connected to MSLN-CAR plus a PD-1 dominant negative mutant, with the target being MSLN (not CD44); moreover, the connection between its TIM3 scFv and the intracellular signaling domain does not adopt a T2A peptide, and the compatibility between the TIM3 scFv and the CD44-CAR intracellular signaling domain is not verified..” (Remarks, pg 9, ¶ 4)
Instant claim 3 uses inclusive or open-ended language. Specifically, claim 3 recites “contains” deemed synonymous with “comprising” which does not exclude additional, unrecited elements (see MPEP 2111.03 (I)). Therefore, the multicistronic vector as taught by the combined teachings of Adusumilli, Xu, and Wu, despite teaching additional domains is still within scope of the instant claims as additional domains are not excluded (i.e. Adusumilli teaches an anti-TIM3 scFv fused via T2A peptide), and as discussed above conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019).
Applicant states:
“The examples of the present application demonstrate that the CAR-T cells expressing the fusion protein of Claim 17 (CAR-T 6) achieve a lysis rate of 86.76% against CD44-positive glioma stem cells at an effector-to-target ratio of 5: 1. This potent and unexpected cytotoxicity is attributable to the specific and synergistic combination of elements claimed, and could not have been predicted from the prior art which teaches only simple substitutions or unrelated
combinations. (Remarks, pg 10, ¶ 2)
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., cytotoxicity) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Bondanza, Xu, and Wu as applied to claim 3 above, and further in view of WO 2018/161017 A1 (herein Suri).
The combined teachings of Bondanza, Xu and Wu teach a fusion protein according to claim 3 as discussed above.
As discussed above the combined teachings of Xu and Wu teach an anti-CD44 scFv identical to instant SEQ ID NO:1 (AA 1-246 of instantly claimed SEQ ID NO:3). While Bondanza teaches a CAR comprising CD28 and CD3 zeta sequences (SEQ ID NO:16), there are several differences within the amino acid sequence in comparison with instant claim sequences (see alignment with SEQ ID NO:3 below, which shares the closest % identity).
SEQ ID NO:3 (Query) aligned with Bondanza SEQ ID NO:16 (Sbjct)
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Suri teaches chimeric antigen receptors are generally composed of an extracellular targeting domain, a transmembrane domain, and an intracellular signaling domain wherein these components are linearly constructed in a single fusion protein, but Suri teaches additional elements can be added or modifications can be made to this fusion polypeptide to develop more competent and safer architecture (¶ [00198]). These additions include hinge domains between extracellular targeting domain and TMD (e.g. CD8α; ¶ [00199]), co-stimulatory domains (e.g. CD28; ¶ [00214]), and functional signaling domains (e.g. CD3 zeta and IL7Rα ¶ [00213]-[00215]). Suri teaches sequences for these fragments that when fused would anticipate the CD8α hinge-TMD (SEQ ID NO:625), CD28 costimulatory domain (SEQ ID NO:297), and CD3ζ intracellular domain (SEQ ID NO: 339) of instant fusion protein encoded by SEQ ID NO:3.
SEQ ID NO:3 (Query) aligned with fusion of Suri SEQ ID NOs: 625, 297, and 339 (Sbjct)
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that domains and corresponding amino acid sequences for respective fusion protein TMD and intracellular signaling domain as taught by the combination of Bondanza, Xu, and Wu can be substituted by any known alternative domains as taught by Suri to arrive at instantly claimed amino acid sequences (e.g. SEQ ID NO:3). Furthermore, a skilled artisan would be motivated to try known alternative domains because Suri teaches variation of hinges and costimulatory domains may improve receptor competency and architecture.
(I) Response to Arguments:
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant states:
“Bondanza, Xu, Wu, and Suri each disclose different aspects of CAR technology;
however, none of these individual documents, nor any combination thereof, renders the claimed invention obvious… The technical solutions of Bondanza, Xu, and Wu differ from Suri' s alternative domains in terms of application scenarios and functional requirements, meaning that a person skilled in the art could not directly combine them. Furthermore, the combination of Bondanza, Xu, Wu, and Suri can only achieve the basic functions of conventional CARs and cannot attain the efficacy of the fusion protein as defined in Claim 13 of the present application. (Remarks, pg 10-11, page spanning ¶)
In response to applicant’s argument, "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. Suri teaches additional elements can be added or modifications can be made to CAR constructs (i.e. implicit modular structure). Therefore, a person of ordinary skill would recognize various CAR elements with known sequences can be substituted with a reasonable expectation of success depending on design goals.
With regard to design efficiency of the recited CAR sequences, these features (i.e. functional activity aside from CD44 binding) are not recited in the claims, and therefore do not hold bearing on the rejection of record. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Bondanza, Xu, and Wu as applied to claim 4 above, and further in view of WO 2018/161017 A1 (herein Suri), US 7,169,894 B2 (herein Martin) and Gould (Front Bioeng Biotechnol. 2014;2:41).
The combined teachings of Bondanza, Xu, and Wu teach a fusion protein with an anti-CD44 scFv antigen binding domain corresponding to instant SEQ ID NO:1 as discussed above.
As discussed above in the rejection of claim 13, the substitution of respective domains of TMD and intracellular sequences as taught by the combined teachings of Bondanza, Xu, and Wu with alternative known CAR elements as taught by Suri render obvious the amino acid sequence of instant SEQ ID NO: 3, which is encoded by the nucleic acid sequence of instant SEQ ID NO: 9.
While Bondanza, Xu, Wu, and Suri do not disclose the full claimed nucleic acid sequence (instant SEQ ID NO:9), reverse translation between amino acid sequences and the nucleic acids that encode them was routine in the art prior to the effective filing date of the claimed invention.
The teachings of Martin and Gould are discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have used the amino acid sequences disclosed by the combination of Bondanza, Xu, Wu, and Suri to arrive at the instantly claimed nucleic acid (e.g. SEQ ID NO: 9) using reverse translation that was known and routine in the art as disclosed by Martin and Gould. An ordinarily skilled artisan would have been able to pursue the known potential solutions with a reasonable expectation that the resulting nucleic acid would encode the amino acid sequence that it was reverse translated from, specifically the CAR disclosed by the combination of the applied references.
(I) Response to Arguments:
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant states:
“…none of the three references discloses the fusion nucleic acid sequences corresponding to SEQ ID NO. 9-13 in Claim 15, nor do they involve the specific nucleotide combination of the CD28, truncated IL7Ra, CD3, and other domains in the fusion protein.” (Remarks, pg 11, ¶ 2)
In response to applicant’s argument, the instant claim is drawn to a list of nucleic acid sequences comprising various combination of domains. This list includes species with IL7Rα (SEQ ID NOs: 11 and 13), species with an anti-TIM3 scFv (SEQ ID NOs: 12 and 13), and species with neither (SEQ ID NOs: 9 and 10). As the claim qualifies the list with “or,” prior art need only teach one species to anticipate the claim. As discussed in the rejection of record the combined teachings of Bondanza, Xu, Wu, and Suri to arrive at the instantly claimed amino acid sequence of SEQ ID NO: 3. Martin and Gould teach reverse translation as well known and routine in the art and there are a finite number of potential solutions in generating a corresponding nucleic acid sequence. Therefore, a skilled artisan would have a reasonable expectation in generating a nucleic acid sequence with identity to instant SEQ ID NO:9 (encoding SEQ ID NO:3).
Applicant states:
“…The fusion proteins encoded by SEQ ID NO. 9-13 of the present application (i.e., SEQ ID
NO. 3-7) exhibit excellent cytotoxic activity in the killing assay against CD44-positive tumor
cells... This effect cannot be anticipated from a combination of the prior art.” (Remarks, pg 11, ¶ 5)
With regard to cytotoxic activity of the recited CAR sequences, these features are not recited in the claims, and therefore do not hold bearing on the rejection of record. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
New Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Bondanza, Xu, and Wu as applied to claim 3 above, and in further view of Huang (Exp Ther Med. 2020;19(1):192-204) and WO 2018/161017 A1 (herein Suri).
The combined teachings of Bondanza, Xu and Wu teach a fusion protein according to claim 3 as discussed above.
None of the aforementioned references discuss antigen binding domain further comprising an anti-CD133 scFv.
Huang teaches that CD133 and CD44 are specific markers expressed by lung cancer-initiating cells, and that simultaneously targeting multiple subsets of cancer-initiating cells can increase cancer-therapeutic efficiency (Abstract).
Suri teaches chimeric antigen receptors are generally composed of an extracellular targeting domain, a transmembrane domain, and an intracellular signaling domain wherein these components are linearly constructed in a single fusion protein, but Suri teaches additional elements can be added or modifications can be made to this fusion polypeptide to develop more competent and safer architecture (¶ [00198]). These additions include additional targeting domains (i.e. bispecific tandem CARs, etc.; ¶ [00234]), which utilize a tandem scFv antigen binding domain.
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the combined teachings of Bondanza, Xu and Wu to generate a bispecific construct comprising a bispecific anti-CD44 and anti-CD133 tandem scFv CAR (i.e. fusing an additional anti-CD133 scFv from a finite number of known sequences) as taught by Suri, and would be motivated to do so because Huang teaches simultaneous targeting of these antigens can increase effectiveness of therapeutics for certain cancers.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Bondanza, Xu, and Wu as applied to claim 3 above, and in further view of Krawczyk (Cancer Immunol Res. 2019;7(4):683-692).
The combined teachings of Bondanza, Xu and Wu teach a fusion protein according to claim 3 as discussed above.
None of the aforementioned references discuss an IL7Rα derived endodomain.
Krawczyk teaches IL-7 signaling is integral to T-cell homeostasis (i.e. cell persistence), and plays a non-redundant role in the maintenance of memory T cells and supports their intermittent proliferative bursts (pg 683, right column, ¶ 2). Krawczyk teaches a CAR coupled with an IL-7Rα intracellular domain (anti-CD123 scFv fused to TMD and intracellular domain of IL7Rα - pg 684, left column, ¶ 3) was sufficient to activate cytokine-independent downstream signaling (i.e. TAA recognition dependent IL7Rα activation) (Figure 4) and that coupling TCR (i.e. a CAR with CD3 intracellular domain) and IL7Rα activation improves anti-tumor activity in vivo and in vitro (Figure 5 and 6).
One of ordinary skill in the art would recognize that incorporating immunomodulatory agents as taught by Krawczyk could improve effectiveness of CAR-T therapies. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that a fusion protein as taught by the combined teachings of Bondanza, Xu and Wu can further be modified with additional immunomodulatory agents such as an IL7Rα endodomain as taught by Krawczyk, and a skilled artisan would be motivated to do so because Krawczyk teaches inclusion of this domain can improve anti-tumor activity of engineered T cells without the need for systemic administration of cytokines (i.e. cytokine independent T cell survival signaling).
Maintained/Modified 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 1-4, 11, 13, 15, and 18-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 and 14 of copending Application No. 18/018,711 (herein US711). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding Claims 1, 3, 13, and 18-19, Claim 13 of US711 claims a fusion protein SEQ ID NO:3, which comprises from N- to C-terminus the following disclosed domains: CD44scFv-CD133scFv-CD28-CD3-T2A-TIM3scFv (¶ [0050]). This construct comprises an anti-CD44 scFv identical to instant claim 1 (SEQ ID NO:1) and comprises a sequence with 100% identity to instant SEQ ID NO:4. This construct further anticipates a fusion protein thereof sequentially linked to an additional CD133 scFv, a TMD, and intracellular signaling domain comprising an anti-TIM3 scFv.
Regarding claims 2, 4, 11, and 15, claim 14 of US711 further claims the nucleic acid sequence shown in US711 SEQ ID NO:4, which comprises a nucleic acid sequence for the fusion protein disclosed in US711 claim 13 comprising a nucleic acid sequence for an anti-CD44 scFv and fusion protein identical to the instant claims (SEQ ID NO:2 and 10, respectively).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4, 11, and 18-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 and 14 of copending Application No. 18/019,010 (herein US010). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding Claims 1, 3, and 18-20, Claim 13 of US010 claims a fusion protein SEQ ID NO:3, which comprises from N- to C-terminus the following disclosed domains: CD44scFv-CD133scFv-CD28-IL7Rα-CD3 (¶ [0048]). This construct comprises an anti-CD44 scFv identical to instant claim 1 (instant SEQ ID NO:1) and further anticipates a fusion protein thereof sequentially linked to an additional CD133 scFv, a TMD, and intracellular signaling domain comprising an IL7Rα domain.
Regarding claims 2, 4, and 11 (dependent on claim 1), claim 14 of US010 further claims the nucleic acid sequence shown in SEQ ID NO:4, which comprises a nucleic acid sequence for the fusion protein disclosed in US010 claim 13 comprising a nucleic acid sequence for an anti-CD44 scFv identical to the instant claims (instant SEQ ID NO:2).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(I) Response to Arguments (No. 13 and 14)
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
In response to applicant’s argument, double patenting rejections are based on a comparison of the claims. 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). Further, in determining whether a nonstatutory double patenting rejection is appropriate, the examiner must compare the overall appearance of the claimed design in the application with the overall appearance of the claimed design in the conflicting application or patent. The claim in the patent or conflicting application must be considered as a whole, i.e., the elements of the claimed design of the reference are not considered individually as they may be when establishing a prima facie case of anticipation under 35 U.S.C. 102 or obviousness under 35 U.S.C. 103. See MPEP § 804, subsection II.B. (information on the analysis for nonstatutory double patenting rejections).
As discussed in the rejections above, the instant claims are anticipated by the claims of each copending application when considered as a whole. While not identical, the claims are within scope of one another and therefore are considered patentably indistinct. Accordingly, the grounds of rejection are maintained (or modified as necessitated by applicant’s amendment).
It is further noted that Applicant’s request that the above rejections be held in abeyance is improper, because “[o]nly compliance with objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated.” MPEP § 804.
Claims 14 and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 and 14 of copending Application No. 18/019,010 (herein US010), in view of WO 2018/165228 A1 (herein Adusumilli), US 11,390,674 B2 (herein Lindsted), Shan (J Immunol. 1999;162(11):6589-6595), Andrews (Immunity. 2019;51(2):398-410.e5), and Koenig (PNAS USA. 2017;114(4):E486-E495).
The instant claims are drawn to an amino acid sequence (instant SEQ ID NOs:8) and corresponding nucleic acid sequence (instant SEQ ID NOs: 14) encoding a fusion protein according to instant claim 3 comprising the following domains: CD44scFv-CD133scFv-CD28-IL7Ra-CD3-2A-TIM3scFv (¶ [0037]).
Claims 13-14 of US010 as discussed above, claim fusion protein amino acid (US010 SEQ ID NO:3) and nucleic acid sequence (US010 SEQ ID NO:4) comprising the following domains with identical sequences to respective domains from instant SEQ ID NO:8 without intracellular 2A-TIM3 scFv: CD44scFv-CD133scFv-CD28-IL7Ra-CD3.
The teachings of Adusumilli are discussed above.
Regarding the specific TIM3 scFv amino acid/nucleic acid sequences, Lindsted teaches an anti-TIM3 antibody with VH/VL amino acid and nucleic acid sequences identical to the respective TIM3 scFv residues within instant SEQ ID NO:8 in all but one framework residue and GS linker (Lindsted sequences aligned with instant SEQ ID NO:8 (AA 862-1093) shown below).
SEQ ID NO:8 (Query) aligned with fused Lindsted SEQ ID NOs: 3 and 4 (Sbjct)
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288
745
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Shan teaches scFv molecules can be generated through fusion of VH and VL regions fused through synthetic peptide linkers consisting of stretches of glycine (G) and serine (S) residues amino acid segments (page 6589, column 2, ¶ 1). In testing linker peptides of 15, 10, and 5 residues consisting of (GGGGS)3, (GGGGS)2, and (GGGGS)1, respectively, Shan observed the single linker (GGGGS) demonstrated superior binding to target antigen (abstract).
Andrews teaches an immunoglobin heavy chain region that contains Q16H VH framework residue (see alignment below).
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208
773
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Koenig teaches that single nucleotide switch at VH residue 16, specifically Q to H, would not significantly impact antibody stability (Figure 1A shown below; annotated with box around residue 16 and dashed arrows indicating boxes that correspond to relevant amino acids).
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825
1630
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the sequences of VH and VL for a known anti-TIM3 antibody can be used to generate an scFv using known methods as taught by Lindsted. Routine optimization would prompt a skilled artisan to utilize a known synthetic peptide linker (GGGGS) which has been shown to improve antigen binding as taught by Shan. Furthermore, simple substitution of an amino acid in non-critical framework residue Q16H as taught by Andrews, that would not greatly impact overall antibody stability as taught by Koenig, would have a reasonable expectation of success for binding to target antigen TIM3. Combining these known elements according to known methods would yield an scFv that would predictably bind TIM3 and thus generating a multicistronic construct from the amino acid sequence disclosed by US010 with a known 2A-TIM3scFv intracellular domain as taught by Adusumilli with amino acid sequences for a known TIM3 scFv as taught by the combined teachings of Lindsted, Shan, Andrews and Koenig would have lead a skill artisan to arrive at the instantly claimed amino acid (SEQ ID NO:8) and corresponding nucleic acid (SEQ ID NO:14).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(I) Response to Arguments - (No. 15)
Applicant's arguments filed 12/16/2025 have been fully considered but they are not persuasive.
Applicant states:
“…The technical solutions of Claims 14 and 16 are essentially different from Application
No. 18/019,010 due to the "addition of the TIM3scFv module plus dual-mechanism synergy", and thus do not constitute nonstatutory double patenting. Meanwhile, none of the cited
references disclose the core technical features, nor do they provide effective inspiration for
combination..” (Remarks, pg 17, page spanning ¶)
In response to applicant’s argument regarding the addition of an intracellular TIM3 scFv module, the secondary references provide the rational and sequences corresponding to these features within the recited sequences (see the rejection of record). Briefly, based on the known benefits of adding a TIM3 scFv within a CAR construct as taught by Adusumilli, it would be obvious that a skilled artisan with the pooled teachings of Lindsted, Shan, Andrews, and Koenig, would be an obvious variation of the invention defined in the instant claims (See MPEP 804(II)(B)(3)).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647