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/CN2021/109849, filed on 07/30/2021. This application claims priority to [PEOPLE'S REPUBLIC OF CHINA Application No. CN202010760969.4, filed 07/31/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
The Amendment, filed on 12/03/2025, is acknowledged in which: claims 8-9 and 12 are canceled; claim 6 is currently amended; claims 1-5, 10-11, and 13-15 were previously presented; claim 7 is original; and claims 16-18 are new.
Claims 1-7, 10-11, and 13-18 are pending in the instant application and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action dated 09/19/2025,
The specification was objected to for using a trademark without a proper symbol indicating use in commerce. Applicant’s submission of an amended specification with appropriate correction has overcome the objection and the objection is withdrawn.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 Applicant’s amendment to the claim has overcome the objection and the objection is withdrawn.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.
New Claim Rejections - 35 USC § 112(b)
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 17 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
As the base claim (claim 3) recites a fusion protein comprising an anti-TIM3-scFv, it is unclear if claim 17 recites (a) the fusion protein of claim 3 with an additional anti-TIM3-scFv separated by T2A peptide or (b) is intended to specify that the fusion protein further comprises a T2A peptide linking the intracellular domain and anti-TIM3-scFv of the base claim. For examination purposes examiner has interpreted the claim under scenario (b) as the disclosure does not speak to fusion proteins with multiple intracellular scFvs.
New Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claim 18 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter (new matter) which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a New Matter rejection.
Applicant references support for new claims 16-18 may be found in ¶ [0035] (Remarks, filed 12/03/2025, ¶ 5). However, the referenced paragraph does not appear to provide adequate written description of the following newly added limitation: “wherein the intracellular signaling domain further comprises IL7Rα or a truncated form thereof” as recited in claim 18. Moreover, the examiner was unable to identify support for the newly added limitation elsewhere in the disclosure.
The amended claims now recite limitations which were not clearly disclosed in the specification or claims as filed, and change the scope of the instant disclosure as filed. These limitations introduce new concepts and violate the description requirement of 35 U.S.C. 112(a). Applicant is required to cancel the New Matter in the response to this Office Action. Alternatively, Applicant is invited to clearly point out the written support for the newly added limitations.
Maintained or 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.
Claims 1, 2, and 11 stand rejected under 35 U.S.C. 103 as being unpatentable over 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).
Regarding claim 1, Lindsted teaches an anti-TIM3 antibody or antigen binding portion thereof, wherein the antibody comprises a set of six CDRs (SEQ ID NO: 7-12) that are within instant SEQ ID NO:1. Lindsted further teaches variable heavy and variable light domains (VH and VL, respectively) which are identical to those within instant SEQ ID NO:1 in all save one framework residue (see alignment below; CDRs underlined and sequence differences highlighted). Lindsted defines an “antigen-binding portion” to include scFv, wherein the VH and VL are fused via synthetic linker (column 15-16 spanning ¶). Lindsted further teaches a traditional scFv linker used in the art is an amino acid sequence comprising (Gly4-Ser)3 (column 34, ¶ 2).
Lindsted VH and VL (SEQ ID NO: 3 and 4, respectively aligned with Instant SEQ ID NO:1
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Lindsted does not teach histidine in place of glutamine at VH framework residue 16 (Q16H) nor single (Gly4-Ser) linker according to instant SEQ ID NO:1.
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 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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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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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 the invention as a whole is obvious over the references (See MPEP § 2143).
Regarding claims 2 and 11, which depend from claim 1, the combined teachings of Lindsted, Shan, Andrews, and Koenig teach claim 1 as discussed above. One of ordinary skill in the art would recognize that standard known methods of reverse translation as taught by Lindsted (column 81-82 spanning ¶) can be employed to generate a nucleic acid sequence from the scFv amino acid sequence according to the combined teachings of Lindsted, Shan, and Andrews (i.e. SEQ ID NO:2).
(I) Response to Arguments:
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant states:
“Lindsted only discloses the scFv form of the anti-TIM3 antibody and the (Gly4-Ser)3 linker, without mentioning the Q16H mutation. Although Shan discloses that a single (Gly4-Ser) linker improves the binding activity of scFv, this disclosure is directed to anti-CD20 antibodies. Although Andrews and Koenig refer to the Q16H mutation, they have no connection to anti-TIM3 antibodies” (Remarks, pg 6, ¶ 7)
“In the prior art, no document teaches or suggests combining the scFv of the anti-TIM3
antibody with the Q16H mutation and the single (Gly4-Ser) linker. These documents belong to independent technical fields such as "basic antibody sequences", "universal linkers", "antibody mutations for other targets", and "mutation stability verification". A person skilled in the art would have no reason to combine them for the design of anti-TIM3 scFv, and there is no obvious motivation for combination” (Remarks, pg 6-7, page spanning ¶)
“Although the CDR sequence of Lindsted overlaps with SEQ ID NO: 1 of the present invention, and the VH/VL framework differs by only one residue, after combining the Q16H mutation and the single (GGGGS)l linker, the overall sequence of SEQ ID NO: 1 would be different from any anti-TIM3 antibody sequence disclosed in the art.” (Remarks, pg 7, ¶ 2)
In response to applicant’s argument regarding the (Gly4-Ser) linker disclosed by Shan, the test for obviousness does 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 a TIM3-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).
In response to applicant's argument that the references are “independent technical fields,” 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, the all 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 TIM3.
In response to applicant’s argument that there is ‘no reason to combine’ or ‘no obvious motivation for combination’, 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 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. Further, office personal are directed to consider whether one or more of other rationales set forth supports a conclusion of obviousness (see MPEP 2141(III)). 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.
Briefly, Lindsted teaches a TIM3 scFv that differs from the instant sequence in the linker sequence and a single framework residue (residue 16 on the VH domain). Shan teaches using a shorter (Gly4-Ser) as opposed to a longer linker (e.g. (Gly4-Ser)3 encoded within the TIM3 scFv as suggested by Lindsted) improves antigen binding in an alternative scFv. Therefore, this would have led a skilled artisan to modify the scFv as taught by Lindsted to substitute the linker as taught by Shan because Shan teaches that a smaller linker sequence could improve antigen binding in an scFv (i.e. routine optimization).
Regarding the single framework residue, a skilled artisan would recognize that antibodies are naturally subject to somatic hypermutations as taught by Koenig. Further, Andrews teaches the presence of a histidine in place of glutamine at residue 16 within a naturally occurring antibody sequenced from patient-derived B cells (VH Sequence ID: QGT37421.1). Koenig further teaches a framework Q16H substitution does not impact antibody stability. Therefore a skilled artisan would recognize simple substitution of a glutamine framework residue as taught by Lindsted at residue 16 for a naturally occurring histidine residue as taught by Andrews would have a reasonable expectation of success because Koenig teaches this substitution would have neutral effects to antibody stability.
Applicant states:
“Moreover, the specific combination of the present invention produces unexpected technical effects. As shown in Example 3 (Table 1) of the Specification, the CAR-T cells (CAR-T 1) containing this specific anti-TIM3 scFv exhibit significantly enhanced tumor cell-killing ability. This indicates that combining the Q16H mutation with the single (GGGGS)l linker produces a synergistic effect for the TIM3 target, which cannot be reasonably expected by a person skilled in the art based on the art.” (Remarks, pg 7, ¶ 2)
In regards to applicant’s allegations of unexpected results, applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). Applicant references Table1 in the instant specification, which references lysis rates of T-cells transfected with a bicistronic vector encoding a bispecific CD44-CD133 targeting CAR and an anti-TIM3 scFv, a vector encoding only the bispecific CD44-CD133 targeting CAR, or empty vector. This data, however, is not relevant to claims 1, 2, and 11 as the instant claims are solely drawn to an anti-TIM3 scFv and amino acid or nucleic acid sequences thereof; objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support (See MPEP 716.02(d)). Evidence of unexpected data should be in the form of direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977).
Applicant states:
“…although there is a conventional technique in the prior art for reverse translating an amino acid sequence to obtain a nucleic acid sequence, the nucleic acid sequence of SEQ ID NO: 2 of the present invention is not a simple product of reverse translation. The codon selection has been optimized to ensure the efficient expression of the anti-TIM3 single-chain antibody in host cells, and this optimization is not disclosed in the prior art.” (Remarks, pg 7, ¶ 3)
In response to applicants argument, 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. 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) (See MPEP 2143.02). Further, when there is a design need 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). In this case, the combination of Lindsted, Shan, Andrews, Koenig render obvious the amino acid sequence of the instantly claimed anti-TIM3 scFv. 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 implied by Lindsted (i.e. some degree of predictability). Therefore, an ordinarily skilled artisan through routine optimization would have been able to reverse translate a corresponding nucleic acid sequence (e.g. SEQ ID NO: 2) with a reasonable expectation of success.
Claims 3-7, 10, 15 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Lindsted, Shan, Andrews, and Koenig as applied to claim 1 above, and further in view of WO 2018/165228 A1 (herein Adusumilli).
The combined teachings of Lindsted, Shan, Andrews, and Koenig teach claim 1 as discussed above.
However, none of the aforementioned references teach a fusion protein chimeric antigen receptor (CAR), wherein the CAR contains an intracellular TIM-3 scFv.
Adusumilli teaches a multicistronic vector (nucleotide sequence elements engineered into an SFG γ-retroviral vector; ¶ [00370]), which encodes for a CAR (MSLN-CAR, comprising an MSLN scFv antigen binding domain, transmembrane domain and 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 in cancer an pathogenic infections; ¶ [0005]-[0006]) (Example 1; Figure 1 - shown below). Adusumilli also teaches suitable 2A peptides to include P2A, T2A, E2A, and F2A peptides, or an alternative IRES can be used (¶ [00164]); and teaches other cancer antigens for CAR targeting as suitable alternatives to MSLN (i.e. depending on cancer expression), including CD133 (¶ [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 T cell populations expressing said vector within pharmaceutical composition for treatment of cancer (¶ [00319] and [00379]).
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One of ordinary skill in the art would recognize the modular nature of multicistronic vectors. 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 the TIM-3 scFv within the construct as taught by Adusumilli could be substituted for any known TIM-3 scFv, such a sequence as taught by the combined teachings of Lindsted, Shan, Andrews, and Koenig, and that alternative targeting domains (e.g. substituting anti-MSLN for an anti-CD133) can be used with a reasonable expectation of success. Furthermore, a skilled artisan would be motivated to generate said multicistronic vector to include immune checkpoint inhibitor (e.g. TIM-3 scFv) separated by a 2A peptide (e.g. T2A) as taught by Adusumilli to overcome immunosuppressive signaling within the tumor microenvironment.
(I) Response to Arguments:
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant states:
“The TIM3 scFv in Adusumilli is a secreted protein expressed independently and separated from CAR via a 2A peptide, which functions as a free immune checkpoint inhibitor. In contrast, the present claims explicitly require that TIM3 scFv is directly fused as part of the intracellular signaling domain of CAR, forming a single multifunctional fusion protein. This structural difference leads to fundamentally different functional mechanisms.” (Remarks, pg 8, pg spanning ¶)
In response to applicant’s argument, The Patent and Trademark Office ("PTO") determines 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).
Regarding claim 3, the instant claim recites “[a] fusion protein, wherein the fusion protein contains an antigen binding domain, a transmembrane domain, and an intracellular signaling domain (ICD) that are sequentially linked; the amino acid sequence of the [ICD] comprises the amino acid sequence of the anti-TIM3 [scFv] according to claim 1.” (emphasis added)
Regarding claim 5, the instant claim recites “[an] expression cassette comprises a first nucleic acid fragment encoding an antigen binding molecule and a second nucleic acid fragment encoding an intracellular signaling molecule, the intracellular signaling molecule contains the anti-TIM3 [scFv] according to claim 1, and an IRES element or a 2A peptide [inserted between the first and second nucleic acid fragments].” (emphasis added)
Both claims use inclusive or open-ended language. Specifically, the term “comprises” is inclusive and does not exclude additional, unrecited elements or method steps (see MPEP 2111.03). As the claims are read in light of the specification, which only discloses an embodiment with T2A separating CD3 and an anti-TIM3 scFv (¶ [0050]; SEQ ID NO: 3 - also implied based on dependent claims 13 and 14), it would be reasonable to interpret the intracellular signaling domain to include additional elements (e.g. CD3 and T2A domains) as they are not excluded from the claim (i.e. 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)).
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., TIM3 scFv directly participating in intracellular signal transduction/functional integration) are not recited in the rejected claims and are not supported by the evidence provided in the specification.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Lindsted, Shan, Andrews, Koenig, and Adusumilli as applied to claim 3 above, and further in view of Huang (Exp Ther Med. 2020;19(1):192-204), WO 2008/079246 A2 (herein Xu), US 8,722,858 B2 (herein Yoshida), Wu (Protein Eng. 2001;14(12):1025-1033), Szymczak (Expert Opin Biol Ther. 2005;5(5):627-638), WO 2018/161017 A1 (herein Suri), Yan (Anal Biochem. 2010;399(1):144-146) and US 11,446,398 (herein Barrett).
The combined teachings of Lindsted, Shan, Andrews, Koenig, and Adusumilli are as discussed above. Adusumilli also teaches alternative suitable targetable cancer antigens (i.e. in place of MSLN), including CD44 or CD133 (¶ [00242]).
However, none of the aforementioned references disclose a full fusion protein with an amino acid sequence according to instant SEQ ID NO:3, which encodes a bispecific CD44 and CD133 chimeric antigen receptor fused via 2A peptide to the TIM3 scFv discussed above (i.e. from N- to C-terminus: CD44scFv, GS linker, CD133scFv, CD8α hinge-TMD, CD28 costimulatory domain, CD3 zeta intracellular domain, T2A peptide, IFN-β signal sequence (AA 1-21), and TIM3 scFv) (instant specification, ¶ [0035]; and examiner sequence analysis).
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).
Xu teaches a monoclonal anti-CD44 antibody with VH (SEQ ID NO:11) and VL (SEQ ID NO:15) amino acid sequences that are identical to those within the instant claimed fusion protein (SEQ ID NO:3 AA 1-121 and 140-246, respectively; see alignment below) and corresponding nucleic acid sequences (SEQ ID NO:12 and 16). Xu further teaches the antibody can be made as an scFv by fusing VH with VL via synthetic linker (page 7, lines 25-27).
SEQ ID NO:3 (Query) aligned with fusion of Xu SEQ ID NOs: 11 and 15 (Sbjct)
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Yoshida teaches a monoclonal anti-Promin-1 (CD133) antibody VH and VL amino acid (SEQ ID NOs: 32 and 34 as disclosed in Figure 8 (variable domains)) and nucleic acid (SEQ ID NOs: 31 and 33, respectively) sequences that are identical to those within the instant claimed fusion protein (see amino acid alignment below). Yoshida further teaches the antibody can be a fragment including scFv (column 12, line 56).
SEQ ID NO:3 (Query) aligned with fusion of Yoshida SEQ ID NOs: 32 and 34 according to Fig 8 (Sbjct)
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Wu teaches design and construction of an scFv by fusing long an flexible joint between VL and VH domains using synthetic linker “GS18” (page 1026, column 1, ‘Design and construction of anti-CD20 scFv-Fc’). This peptide sequence is identical to the linker used in CD44 and CD133 scFv disclosed within instant SEQ ID NO:3 (highlighted in respective alignments above).
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]), 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 (see alignment below). Suri further teaches “armed” CAR T cells which are transformed with effector module comprising a CAR and an effector module comprising a cytokine to improve efficacy and persistence (¶ [00343]).
SEQ ID NO:3 (Query) aligned with fusion of Suri SEQ ID NOs: 625, 297, and 339 (Sbjct)
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Szymczak teaches functional 2A-peptide sequences for use in multicistronic vector construction, which are ideal for efficient coexpression of a wide variety of proteins with different subcellular localization (page 631, ¶ 2-3), with an amino acid sequence identical to residues 728-745 of instant SEQ ID NO:3 (Table 2, TaV sequence).
Yan teaches that proteins downstream of 2A cleavage sequences in multicistronic vectors do not undergo slipstreaming (automatic translocation to the ER for secretion) in mammalian cells, and that N-terminal signal sequences are needed for proper compartmentalization (Abstract; page 144, column 2, ¶ 2).
Barrett teaches regulatable and tunable biocircuit systems which comprise at least one effector module defined as a multi-component construct or complex comprising at least (a) one or more stimulus response elements and (b) one or more payloads (column 11, lines 48-53) (e.g. single chain Fv antibodies; column 1431, lines 8-18), which can be separated by cleavable elements (Figure 2). Barrett further teaches that modules can include signal sequences to direct respective peptides to corresponding cellular and extracellular locations encoded therein, including IFNβ signal peptide for secreted proteins identical to residues 746-766 of instant SEQ ID NO:3 (Table 6, columns 1449-1450, SS No. 492; SEQ ID NO: 205859).
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 amino acid sequences known in the prior art as taught by the combined teachings of Lindsted, Shan, Andrews, Koenig, Xu, Yoshida Wu, Suri, Szymczak, and Barrett can be combined according to known molecular cloning methods to arrive at the instantly claimed amino acid construct encoded by SEQ ID NO: 3. An ordinarily skilled artisan would have been motivated to generate a bispecific construct comprising a bispecific anti-CD44 and anti-CD133 CAR and because Huang teaches simultaneous targeting of these antigens can increase effectiveness of therapeutics for certain cancers. Furthermore, a skilled artisan would be motivated to fuse a known secretory single sequence (e.g. IFNβ residues 1-21 as taught by Barrett) to TIM3-scFv downstream of T2A sequence (as taught by Szymczak) because multicistronic vectors do not undergo slipstreaming in mammalian cells as taught by Yan.
(I) Response to Arguments:
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant states:
“The multiple documents cited by the Examiner do not teach or suggest the specific multidomain fusion protein (SEQ ID NO: 3) of the present invention.” (Remarks, pg 8, ¶ 4)
“Huang only states that CD44/CD133 are lung cancer stem cell markers, without mentioning bispecific CAR.” (Remarks, pg 8, ¶ 5)
“Although Xu and Yoshida separately disclose anti-CD44 and anti-CD133 scFv, they do
not involve the tandem connection of the two and the fusion with TIM3 scFv… no single document or reasonably combined documents teach or suggest the specific multi-domain fusion protein of the present invention.” (Remarks, pg 8, ¶ 6)
“The CD44/CD133 scFv linker (GS18) and TIM3 scFv sequence of SEQ ID NO: 3 in the present application are different from the sequences in documents such as Xu and Yoshida, and the improved dual-target binding efficiency brought by these differences is not predicted by the prior art.” (Remarks, pg 8-9 spanning ¶)
In response to applicant's argument that reference cited do not teach or suggest the instant fusion protein nor CD44/CD133 tandem scFvs within a CAR, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that 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).
As discussed above, "[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.
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).
Briefly, Adusumilli teaches multicistronic CAR vectors with a TIM3 scFv can mitigate immune checkpoint inhibition characteristic in cancer, Huang teaches simultaneous targeting of CD133 and CD44 can be beneficial in targeting lung cancer-initiating cells (i.e. predicted benefit of dual targeting CAR), and Suri teaches the feasibility of construction of tandem scFvs as a CAR antigen binding domain (e.g. tandem scFvs ¶ [00164]). Specifically regarding SEQ ID NO:3, the instant sequence comprises sequences known in the prior art as taught by Lindsted, Shan, Andrews, Koenig (TIM3 scFv), in further view of Xu (identical CD44 VH/VL sequences), Yoshida (identical CD133 VH/VL sequences), Wu (identical functional scFv linker), Suri (identical CD8α hinge-TMD, CD28 costimulatory domain, and CD3 intracellular domain), Szymczak (identical 2A peptide sequence), and Barret (identical signal sequence (residues 746-766 of instant SEQ ID NO:3) between T2A and TIM3-scFv to facilitate TIM3 secretion as taught by Yan), and could be constructed into a sequence encoded by a multicistronic vector by one of ordinary skill as suggested by the combined teachings of Adusumilli, Huang, and Suri.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Lindsted, Shan, Andrews, Koenig, Adusumilli, Huang, Xu, Yoshida, Wu, Szymczak, Suri, Yan, and Barrett as applied to claim 13 above, and further in view of US 7,169,894 B2 (herein Martin) and Gould (Front Bioeng Biotechnol. 2014;2:41).
As discussed above in the rejection of claim 13, the combined teachings of Lindsted, Shan, Andrews, Koenig, Adusumilli, Huang, Xu, Yoshida, Wu, Szymczak, Suri, Yan, and Barrett 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: 4.
While the full nucleic acid is not taught by the combined aforementioned refences, 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 Lindsted, Shan, Andrews, Koenig, Adusumilli, Huang, Xu, Yoshida, Wu, Szymczak, Suri, Yan, and Barrett to arrive at the instantly claimed nucleic acids (e.g. SEQ ID NO: 4) 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 multicistronic sequence disclosed by the combination of the applied references.
(I) Response to Arguments:
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant states:
“…codon selection cannot be directly obtained through "conventional reverse translation" in the prior art and involves non obvious design considerations. The specific codon combination of SEQ ID NO: 4 (e.g., codon optimization of key domains) is not disclosed in or suggested by any existing documents, and the effect of improved expression level brought by this sequence is not suggested in the prior art.” (Remarks, pg 9, ¶ 3)
In response to applicants argument, 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. 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) (See MPEP 2143.02). As stated in the rejection of record, an ordinarily skilled artisan would have been able to pursue the known potential solutions (i.e. finite number of codons specific for amino acids as taught by Martin and with optimization tools as taught by Gould) with a reasonable expectation that routine optimization would result in a nucleic acid sequence with identity to SEQ ID NO: 4 encoding the multicistronic sequence disclosed by the combination of the applied references.
New Claim Rejections - 35 USC § 103
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Lindsted, Shan, Andrews, Koenig, and Adusumilli as applied to claim 3 above, and further in view of Krawczyk (Cancer Immunol Res. 2019;7(4):683-692).
The combined teachings of Lindsted, Shan, Andrews, Koenig, and Adusumilli are as discussed above. Adusumilli further teaches the inclusion of immunomodulatory agents to facilitate the effectiveness of cells expressing the disclosed multicistronic vectors (e.g. IL-7) (¶[00345]).
However, none of the aforementioned references disclose an IL-7Rα derived CAR 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 Adusumilli 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 Lindsted, Shan, Andrews, Koenig, and Adusumilli 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 or 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.
US 18/018,764
Claims 1-7, 10-11, and 13-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 10, and 12-16 of copending Application No. 18/018,764 (herein US764). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-3 and 11, the instant claims are drawn to a TIM-3 scFv with specific amino acid sequence and a fusion protein (CAR with extracellular binding domain, transmembrane domain, and intracellular signaling domain sequentially linked) containing said scFv fused to the intracellular portion, which by broadest reasonable interpretation can be any receptor that meets the limitations of the claimed genus of receptor. Claim 3 of US764 claims species of fusion proteins comprising anti-CD44 scFv antigen binding domain, a transmembrane domain, and intracellular signaling domain sequentially linked with an additional intracellular TIM-3 scFv (US764 SEQ ID NOs: 6, 7, and 8). The sequences claimed have an TIM-3 scFv with an amino acid sequence identical to the instant application, and thus the claimed species are within scope of the instant claimed genus of CAR fusion proteins with general antigen binding (target antigen on the surface of a tumor cell; instant specification ¶ [0003]) and/or anti-CD44 scFv domains, rendering the claims patentably indistinct.
Regarding claim 4, claim 4 of US764 claims a nucleic acid sequence corresponding to the fusion protein according to US764 claim 3 (discussed above).
Regarding claim 5 and 15, claim 5 of US764 claims an expression vector with sequence corresponding to US764 claim 4.
Regarding claim 6, claim 6 of US764 claims a cell expressing the vector according to US764 claim 5.
Regarding claim 7, claim 7 of US764 claims the host cell of US764 claim 6 is a T cell.
Regarding claim 10, claim 10 of US764 claims a pharmaceutical composition of the cell expressing the vector according to claim 6 or 7 of US764.
Regarding claims 13-14, and 16-18, the instant claims drawn to amino acid (SEQ ID NO:3) and nucleic acid (SEQ ID NO:4) sequences comprising the following components: CD44scFv-CD133scFv-CD28-CD3-T2A-TIM3scFv (instant specification, ¶ [0035]). Claim 12 of US764 claims a fusion protein according to US764 claim 3, wherein the antigen binding portion comprises the anti-CD44 scFv (from US764 claim 1) and/or anti-CD133 scFv, and the intracellular signaling domain comprises an anti-TIM3 scFv and/or IL7Rα domain. Claims 13-16 of US764 contain amino acid and nucleic acid sequences identical to respective domains as claimed in instant SEQ ID NO:3 and 4. Specifically, claims 13 and 15 of US764 claim amino acid and nucleic acid sequences for a CD44scFv-CD133scFv bispecific fusion protein fused to CD28 and CD3 domains (US764 SEQ ID NOs: 4 and 10, respectively) and a monospecific fusion protein within the following domains: CD44scFv-CD28-CD3-T2A-TIM3scFv (US764 SEQ ID NOs: 6 and 12, respectively). Moreover, claims 14 and 16 of US764 claim amino acid and nucleic acid sequences for a fusion protein of the following domains: CD44 scFv-CD133scFv-CD28-IL7Ra-CD3-T2A-TIM3scFv (SEQ ID NOs: 8 and 14, respectively). A skilled artisan based on the genus of fusion proteins as claimed in US764 claim 12, could envision an embodiment based on the respective sequences as presented in US764 claims 13-16 that would arrive at the instantly claimed amino acid and nucleic acid sequences, and therefore the claims are patentably indistinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
US 18/018,778
Claims 1-3, 11, and 16-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 and 14 of copending Application No. 18/018,778 (herein US778). Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are drawn to a TIM-3 scFv with specific amino acid sequence and a fusion protein (CAR with extracellular binding domain, transmembrane domain, and intracellular signaling domain sequentially linked) containing said scFv fused to the intracellular portion, which by broadest reasonable interpretation can be any receptor that meets the limitations of the claimed genus of receptor. Claims 13 and 14 of US778 claims species of fusion proteins (amino acid and nucleic acid sequences) comprising anti-CD133 scFv antigen binding domain, a transmembrane domain, and intracellular signaling domain (US778 claim 3) with or without an intracellular IL7Rα domain sequentially linked via T2A sequence to an intracellular TIM-3 scFv (US778 SEQ ID NOs: 5 and 6 and corresponding nucleic acid sequences SEQ ID NOs: 9 and 10). The sequences claimed have an TIM-3 scFv with an amino acid sequence identical to the instant application (with identical IL7Rα and/or T2A peptide domains), and thus the claimed species are within scope of the instant claimed genus of CAR fusion proteins with general antigen binding (target antigen on the surface of a tumor cell; instant specification ¶ [0003]) and/or anti-CD133 scFv domains, rendering the claims patentably indistinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(I) Response to arguments - Double patenting
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
a) Applicant states:
“There are obvious differences in patentability between the claims of the present
application and those of US 18/018,764 and US 18/018,778, as they protect different inventive concepts, solve different technical problems, and produce different unexpected synergistic effects.” (Remarks, pg 9, ¶ 5)
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 rejection 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.
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