DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
The response to the restriction/election filed 8 June 2026 is acknowledged. Applicant elects Group I, claim 1-23 and 25-34, drawn to an immunoresponsive cell comprising an NKG2D polypeptide and a fusion polypeptide comprising a DAP10 polypeptide or a functional variant thereof and a DAP12 polypeptide or a functional variant thereof, and a CXCR2 polypeptide without traverse.
Claims 36-49, 51, and 58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8 June 2026.
Applicant further elects the species of fusion protein SEQ ID NO: 60, aa 1-93 of DAP10 (SEQ ID NO: 1) fused to aa 62-113 of DAP12 (SEQ ID NO: 11).
Claims 11-13, 15, 20-22, and 25-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8 June 2026.
Claim Status
Claims 1-23, 25-34, 36-49, 51, and 58 are pending. Claims 11-13, 15, 20-22, 36-49, 51, and 58 are withdrawn. Claims 1-10, 14, 16-19, 23, and 25-34 are under examination in the instant office action.
Priority
The claim to domestic benefit as a 371 of PCT/EP2022/057653 filed 3/23/2022, which claims benefit of 63/164959 filed 3/23/2021 and 63/288593 filed 12/11/2021 is acknowledged. However, provisional application 63/164959 filed 3/23/2021 does not provide any support for an immunoresponsive cell comprising a CXCR2 polypeptide as recited in the instant claims.
Additionally, as described in the 112(a) written description rejection below, claims 1-10, 14, 16-19, 23, and 25-34 are not sufficiently described in the instant specification for the genus as currently required by the instant claims, and therefore the claims are examined with priority to the 371 filing date of 23 March 2022.
Information Disclosure Statement
The information disclosure statements (IDSs) filed 9/21/2023, 4/16/2024, 9/13/2024, 3/28/2025, 7/17/2025, 10/14/2025, and 10/29/2025 have been considered except where lined through. CN113013450 (IDS dated 3/28/2025) and CN109734814 (IDS dated 7/17/2025) have been lined through because no English language abstract or statement of relevance was provided. CN109312304 is not struck through because although no translation was provided, English language equivalent WO2017184901 (PTO-892) was found and considered during the course of examination.
Drawings
The drawings are objected to because the shades of gray in the lines and legends of Figs. 17, 24 are not discernable from one another such that the results can be understood. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 9 is objected to for the recitation “is a DAP1O polypeptide” in line 6, which appears to inadvertently recite the letter “O” rather than the numeral “0” in referring to the polypeptide “DAP10”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1-10, 14, 16-19, 23, and 25-34 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is drawn to an immunoresponsive cell comprising a fusion polypeptide comprising (i) a DNAX-activating 10 (DAP10) polypeptide, or a functional variant thereof and (ii) a DNAX-activating protein 12 (DAP12) polypeptide, or a functional variant thereof; and a CXCR2 polypeptide. However, the function of the recited DAP10 or DAP12 polypeptides is not stated, and DAP10 and DAP12 each have several domains each with distinct functions that contribute to the overall activity of the wildtype peptides. Regarding the definition of DAP10 and DAP12 polypeptides and functional variants thereof, the specification does not have a closed definition of DAP10 or a DAP12 function variant. The specification teaches that the DAP10 and DAP12 polypeptide may be mammalian and gives the example of SEQ ID NO: 1 and SEQ ID NO: 9, respectively and teaches polypeptide having at least about 80% identity to SEQ ID NOs: 1 and 9 ([0082], [0090]).The specification further teaches that “In another embodiment, a functional variant DAP10 polypeptide used in the disclosed may comprising one or more (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) point mutations that add, delete, or substitute any of the amino acids of the amino acids of” DAP10 [0084] or DAP12 [0092]. As such, there is no upper limit on the number of changes that may occur or how small a fragment can be before a polypeptide is no longer considered a DAP10 or DAP12 variant, and the metes and bounds of the claimed fusion protein are unclear.
Claims 5-8 are drawn to an immunoresponsive cell comprising an NKG2D polypeptide, wherein the NKG2D polypeptide is a functional variant of the polypeptide of SEQ ID NO: 14. The claim function of SEQ ID NO: 14 that the variant must possess is not described by the claim. The specification additionally does not offer a definition of the function that must be possess or a limit on the variants: ““In another embodiment, a functional variant NKG2D polypeptide used in the disclosed may comprising one or more (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) point mutations that add, delete, or substitute any of the amino acids of the amino acids of NKG2D (such as that of wild-type human NKG2D (SEQ ID NO: 14))” [00102]. As such, there is no upper limit on the number of changes that may occur or how small a fragment can be before a polypeptide is no longer considered an NKG2D variant, and the metes and bounds of the claimed NKG2D polypeptide are unclear.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 13, 14, 19, 21, 22, 27, 29 recite the broad recitation "comprises", and the claim also recite "consists" which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 16, the parenthetical “(i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more)” renders the claim indefinite because it is unclear whether the limitations within the parenthetical are part of the claimed invention. See MPEP § 2173.05(d). It is suggested the applicant amend the claim to delete the limitations within the parenthetical.
Claim 25 contains the trademark/trade name AviTag™ in line 3. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the peptide tag SEQ ID NO: 49 (See specification [0113]) and, accordingly, the identification/description is indefinite.
Dependent claims are rejected for failing to fully resolve the indefiniteness as described.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 23 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 23, the claim is directed to the fusion polypeptide wherein the fusion polypeptide comprises an N- or a C- terminal sequence. This is not further limiting because all polypeptides comprise both an N- and a C-terminal sequence.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. The Examiner suggests amending the claim to recite that the fusion polypeptide comprises an additional N-terminal or C-terminal polypeptide sequence.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-10, 14, 16-19, 23, and 25-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the claimed genus
The claims are drawn to an immunoresponsive cell comprising a fusion protein comprising DAP10 and DAP12 polypeptides, or functional variants thereof, wherein functional variants include changes with no upper limit to instant SEQ ID NOs: 1 and 9 or at least about 80% identity to SEQ ID NO: 1; or having one or point mutations that add, delete or substitute any of the amino acids of SEQ ID NO: 9 (claim 1 and 10, 15, 16-17) ; a NGK2D polypeptide, wherein NKG2D polypeptides include any generic NKG2D polypeptide such as changes allowing identity of “at least about 80%” to SEQ ID NO: 14 (claims 1, 5-8); and any generic CXCR2 polypeptide, or one having at least about 85% sequence identity to SEQ ID NO: 87 (claims 1 and 31). Accordingly, the claims allow broadly for any and all differences in the amino acid sequences in the fusion protein comprising DAP10 and DAP12; the NGK2D polypeptide; and the CXCR2 polypeptide broadly. Even at the narrowest, the claims allow for 18 residue changes of SEQ ID NO: 1; any length truncation of SEQ ID NO: 9; 43 residue changes in SEQ ID NO: 14; and 54 residue changes in SEQ ID NO: 87.
State of the Relevant Art
The prior art teaches of domains and residues within the C-terminal tails of DAP10 and DAP12 responsible for their signaling capacity, as well as the transmembrane residues that enable DAP10 and NKG2D to interact, and the basic mechanism by which the extracellular domain of NKG2D engages with its ligands (reviewed in Lanier, 2015. Cancer immunology research, 3(6), 575-582; IDS 10/14/2025). While several key residues are known, there is no comprehensive study of the structural or functional contributions of the entirety of the DAP10, DAP12, or NKG2D sequences such that one could reasonably construct or predict functional variants.
Regarding CXCR2, the art teaches that the CXCR2 N terminus CRS1 domain plays a key role in initial recruitment of the ligand CXCL8 and is required for the activity of CXCL8 in a beta-arrestin 2 recruitment assay and that the CRS2 domain is required for CXCR2 activation (Liu, Kaiwen, et al. "Structural basis of CXC chemokine receptor 2 activation and signalling." Nature 585.7823 (2020): 135-140; hereinafter Liu A). Liu A teaches that the coupling of downstream Gi signaling through CXCR2 requires the hydrophobic pocket formed by particular residues. Regarding activation, Liu et. al. teaches “The hydrogen bonds and electrostatic interactions that are formed by Glu4 of the ELR motif and Arg2085.35, Arg2125.39 and Arg2786.62 in the major subpocket act synergistically to trigger the inward movement of the extracellular portion of TM5 by about 6 Å, which is the driving force for CXCR2 activation (Fig. 3b). In confirmation of this, we found that mutating key residues to alanine (Y197ECL2A, R2786.62A, R2125.39A and R2085.35A mutations) reduced the activity of CXCL8 (Fig. 3c)”. Thus, while the structure/activity of the key residues has been explored, it would not have been predictable which substitutions of key residues or of adjacent residues may be made while retaining the function of the CXCR2 polypeptide; and further, which functions are required of the CXCR2 polypeptides are not articulated from the art in a genus commensurate with the instant claims. Immune cells expressing exogenous wild-type CXCR2 for increased trafficking to tumors are known in the art (Jin, Linchun, et al. "CXCR1-or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors." Nature communications 10.1 (2019): 4016, Of Record, IDS dated 9/21/2023).
Summary of Species and Structure/Activity relationships disclosed in the original specification
The instant specification teaches T-cells comprising the construct N1012, which expresses a full-length wild-type human NKG2D of SEQ ID NO: 14, a fusion polypeptide comprising SEQ ID NO: 60, which is full-length human DAP10 fused at the C-terminal domain with the intracellular signaling domain of DAP12, with or without expression of wild-type human CXCR2, SEQ ID NO: 87. These T-cells are compared to cells comprising wild-type NKG2D overexpression alone or overexpression of an NKG2D chimera comprising a NKG2D fused to a CD3-zeta intracellular signaling domain (e.g. Fig. 16). The T-cells are cytotoxic against ovarian cells lines (Fig. 17). The N1012 cells comprising CXCR2 have lower cytokine secretion than N1012 cells (4.7.15 Example 15, [0214] Fig. 22). The constructs were further compared in in vivo ovarian cancer models; N1012 or N1012 and CXCR2 T-cells suppressed tumor growth on rechallenge compared to NKG2D-CD3-zeta positive control construct (Example 17, Fig. 38, [0220]) and suppressed tumor growth in a second model ([0222]). T-cells expressing N1012 and CXCR2 together had increased trafficking to tumors compared to N1012 alone (Example 17, [0224-0225]). There are no alternate immunosuppressive cells comprising all 3 components tested in the specification. The specification prophetically recites other truncations of DAP10 and DAP12 [0085], [0093] and prophetically recites any CXCR2 or NKG2D polypeptides including undefined variants which preserve up to 10% of an undefined function of CXCR2 or NKG2D [0087], [0095].
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for immunoresponsive cells comprising NKG2D polypeptides including undefined functional variants and truncations, fusion protein comprising a DAP10/DAP12 fusion polypeptide comprising undefined functional variants, and CXCR2 polypeptides including undefined functional variants and truncations. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the respectively claimed polypeptides and insufficient description of what functional would be required of each polypeptide to meet the requirements of the claimed genus. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of immunoresponsive cells comprising polypeptides with substitutions and deletions of claim 1 at the time of filing. Regarding claims 2-10, 14, 16-23, and 25-34, the claims are ultimately dependent on the rejected claim 1 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
Claims 1-10, 14, 16-19, 23, and 25-34 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a T-cell or an NK cell comprising an NKG2D polypeptide comprising at least the extracellular domain of NKG2D, a DAP10/12 fusion polypeptides comprising amino acids 62-113 of DAP12 fused C-terminally to full length DAP10 or DAP10 truncations comprising aa19-93, aa19-69, aa1-71, or aa19-71, and a full-length CXCR2 polypeptide, does not reasonably provide enablement for any generic immunosuppressive cell comprising any NKG2D polypeptide or functional variant thereof, any fusion protein comprising a DAP10 and a DAP12 polypeptide or a functional variant thereof, and any CXCR2 polypeptide or a functional variant thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. In In re Wands, 8 USPQ2d 1400 (Fed. Cir., 1988) eight factors included for determining enablement:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The following is an analysis of these factors in relationship to this application.
Scope of the claimed genus and nature of the invention
The claims are drawn to an immunoresponsive cell comprising a fusion protein comprising DAP10 and DAP12 polypeptides, or functional variants thereof, wherein functional variants include changes with no upper limit to instant SEQ ID NOs: 1 and 9 or at least about 80% identity to SEQ ID NO: 1; or having one or point mutations that add, delete or substitute any of the amino acids of SEQ ID NO: 9 (claim 1 and 10, 15, 16-17) ; a NGK2D polypeptide, wherein NKG2D polypeptides include any generic NKG2D polypeptide such as changes allowing identity of “at least about 80%” to SEQ ID NO: 14 (claims 1, 5-8); and any generic CXCR2 polypeptide, or one having at least about 85% sequence identity to SEQ ID NO: 87 (claims 1 and 31). Regarding the definition of “immunoresponsive cell”, the instant specification does not have a definition; as nearly all cells have receptors and respond to stimuli from the immune system such as cytokines, the broadest reasonable interpretation of “immunoresponsive cell” is that it is a cell. Accordingly, the claims allow broadly for any and all differences in the amino acid sequences in the fusion protein comprising DAP10 and DAP12; the NGK2D polypeptide; and the CXCR2 polypeptide broadly. Even at the narrowest, the claims allow for 18 residue changes of SEQ ID NO: 1; any length truncation of SEQ ID NO: 9; 43 residue changes in SEQ ID NO: 14; and 54 residue changes in SEQ ID NO: 87.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art
The prior art teaches of domains and residues within the C-terminal tails of DAP10 and DAP12 responsible for their signaling capacity, as well as the transmembrane residues that enable DAP10 and NKG2D to interact, and the basic mechanism by which the extracellular domain of NKG2D engages with its ligands (reviewed in Lanier, 2015. Cancer immunology research, 3(6), 575-582; IDS 10/14/2025). While several key residues are known, there is no comprehensive study of the structural or functional contributions of the entirety of the DAP10, DAP12, or NKG2D sequences such that one could reasonably construct or predict functional variants. The examiner notes that both T cells and NK cells express endogenous full-length NKG2D which participates in effector cell signaling (See e.g., Li, JieYu, et al. "Dap10 co-stimulation enhances the anti-HCC efficacy of NKp30 chimeric antigen receptor T cells." Translational Oncology 57 (2025): 102425), and therefore both T and NK cells would allow for additional NKG2D polypeptides with truncations such as CARs comprising only the ectodomain of NKG2D.
Regarding CXCR2, the art teaches that the CXCR2 N terminus CRS1 domain plays a key role in initial recruitment of the ligand CXCL8 and is required for the activity of CXCL8 in a beta-arrestin 2 recruitment assay and that the CRS2 domain is required for CXCR2 activation (Liu, Kaiwen, et al. "Structural basis of CXC chemokine receptor 2 activation and signalling." Nature 585.7823 (2020): 135-140). Liu et. al. teaches that the coupling of downstream Gi signaling through CXCR2 requires the hydrophobic pocket formed by particular residues. Regarding activation, Liu et. al. teaches “The hydrogen bonds and electrostatic interactions that are formed by Glu4 of the ELR motif and Arg2085.35, Arg2125.39 and Arg2786.62 in the major subpocket act synergistically to trigger the inward movement of the extracellular portion of TM5 by about 6 Å, which is the driving force for CXCR2 activation (Fig. 3b). In confirmation of this, we found that mutating key residues to alanine (Y197ECL2A, R2786.62A, R2125.39A and R2085.35A mutations) reduced the activity of CXCL8 (Fig. 3c)”. Thus, while the structure/activity of the key residues has been explored, it would not have been predictable which substitutions of key residues or of adjacent residues may be made while retaining the function of the CXCR2 polypeptide; and further, which functions are required of the CXCR2 polypeptides are not articulated from the art in a genus commensurate with the instant claims. Immune cells expressing exogenous wild-type CXCR2 for increased trafficking to tumors are known in the art (Jin, Linchun, et al. "CXCR1-or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors." Nature communications 10.1 (2019): 4016; Of Record, IDS dated 9/21/2023).
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure
The instant application discloses DAP10/DAP12 fusion proteins that form functional chimeric receptor complexes with NKG2D which are capable of driving immune cell-mediated lysis of tumor cells (Examples 1-9). The stated purpose of this fusion is to support full activation of T cells through the NKG2D receptor with both a co-stimulatory signal provided by DAP10 (“signal 2”) and primary signaling through the DAP12 ITAM domain (“signal 1”) (Pg. 1-2; § Background; § Summary of the Invention), both functions requiring the intracellular domains of DAP10 and DAP12 where the important YINM and ITAM motifs, respectively, are localized (see, for example Lanier 2015. Cancer immunology research, 3(6), 575-582.). The instant specification also discloses that high levels of CXCR2 ligands are produced by tumors [0006] but does not explicitly disclose that the purpose of the CXCR2 polypeptide is to increase immune cell trafficking to tumors.
Notably, the only species of DAP10/DAP12 fusion protein reduced to practice comprises full-length DAP10 including its extracellular, transmembrane, and intracellular signaling domains fused at the C-terminus to the DAP12 intracellular signaling domain (part of the “N1012” construct; summarized in Fig. 1; Examples 1-9). Additional exemplary constructs are detailed in Table 2, and the DAP10/DAP12 fusions comprised within each all comprise either the full-length DAP10 or a truncated version comprising only the extracellular domain and the transmembrane domain – without the N terminal signal sequence or C-terminal intracellular signaling domain – fused to the same DAP12 endodomain sequence as in N1012 (Table 2; e.g. “Construct 3”).
The instant specification further discloses that DAP10 is required for proper NKG2D expression (“Each NKG2D homodimer associates with two homodimeric DAP10 adaptor molecules via complementary charged amino acids within the plasma membrane” and “(t)his interaction is required for cell surface expression and function of NKG2D”) (Pg. 1, last ¶). Consistent with this, the prior art teaches that the DAP10 transmembrane domain is both necessary and sufficient for NKG2D localization. For example, Wu et al. 2000 (The Journal of experimental medicine, 192(7), 1059-1068.; IDS filed 09/21/2023) generated chimeric DAP10/DAP12 molecules wherein the transmembrane domain from DAP10 was swapped with that of DAP12, and vice versa. Wu demonstrates that only wild type DAP10 and DAP12 comprising the DAP10 transmembrane domain, but not wild type DAP12 nor DAP10 comprising the DAP12 transmembrane domain, supports surface expression of the NKG2D receptor complex (Pg. 1061, last ¶; Fig. 2).
Accordingly, for the exogenous receptors of the instant disclosure to function, the DAP10/DAP12 fusion protein must contain the DAP10 transmembrane domain critical for NKG2D localization in addition to co-stimulation via phosphatidylinositol 3-kinase provided by the DAP10 intracellular domain and its “YINM” motif (“signal 2”) and an ITAM signal provided by the DAP12 endodomain (“signal 1”). Alternatively, the DAP10 costimulatory signal can be provided separately from the DAP10/DAP12 fusion by co-expression of wild type DAP10 alongside the DAP10/DAP12 fusion lacking the DAP10 intracellular domain as exemplified by the “1012_10_N” receptor complex illustrated in Fig. 1.
It is further unclear from the instant disclosure or the prior art whether DAP10 molecules comprising truncated extracellular domains would be “functional” in the context of the instant invention. While it is routine in the art to substitute signal sequences between different proteins (as would be the case for DAP10 species lacking amino acids 1-18), it is unclear from the prior art or the instant disclosure whether further truncations of DAP10 would support a functional receptor complex. For example, the prior art teaches that DAP10 dimers are required for NKG2D function and localization, and conserved cysteine residues present within the DAP10 extracellular domain contribute to this dimerization (see, for example, Garrity et al. 2005. PNAS, 102(21), 7641-7646.; Pg. 7642, § Stoichiometry of the NKG2D-DAP10 Complex; IDS dated 10/14/2025), and, notably, the only working examples in the specification comprise the complete extracellular domain of DAP10.
As such, a “functional” DAP10/DAP12 fusion having utility commensurate with the instant disclosure must support both localization and signaling through the NKG2D receptor, and only those species comprising the DAP10 extracellular and transmembrane domain (with or without the signal peptide), DAP12 intracellular domain, and DAP10 intracellular domain (either as part of the DAP10/DAP12 fusion or provided separately as wild type DAP10) are enabled by the disclosure. Specifically, the specification is enabling for fusion proteins comprising DAP12 aa62-113 truncation fused C-terminally to the DAP10 full length or truncations consisting of aa19-93, aa19-69, aa1-71, or aa19-71.
Regarding NKG2D polypeptides it is further noted that the instant claims encompass variants and chimeric NKG2D polypeptides for which the interaction with the DAP10/DAP12 fusion protein would additionally be unknown. For example, Lehner, Manfred, et al. "Redirecting T cells to Ewing's sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection." PloS one 7.2 (2012): e31210 (IDS 9/21/2023) teaches an NKG2D CAR-T comprising the extracellular domain of NKG2D fused to IgG1-Fc/CD28/CD3-zeta CAR backbone (“Construction of the chNKG2D” section), and it is not clear what would be required of the DAP10/DAP12 fusion protein to interact with this NKG2D polypeptide which does not have the native NKG2D transmembrane domain in immunoresponsive cells that do not comprise endogenous NKG2D.
Regarding CXCR2 polypeptides, no variants or alternate CXCR2 polypeptides are disclosed except for full-length human CXCR2 comprising SEQ ID NO: 87.
Conclusion
The applicant is not enabled for the full scope of the immunoresponsive cells as claimed because additional species beyond the scope of the working example in the specification would require an undue amount of experimentation to assess their ability to function as part of an NKG2D receptor complex and/or determine alternative useful applications for said fusions.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 4-6, 8-10, 14, 16-19, 23, 28-29, and 33-34 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by U.S. 20200308248 to Liu et. al. published 1 October 2020 and effectively filed 23 March 2020 (IDS dated 9/21/2023) as evidenced by U.S. 20180371051; Uniprot O43914 TYOBP_Human; and Uniprot Q9UBK5 HSCT_Human.
Regarding claim 1, Liu et. al. teaches genetically engineered T cells and natural killer cells comprising constructs which express a chimeric protein comprising human NKG2D and an adaptor protein comprising a DAP10/12 fusion (Abstract, [0009-0011], Fig. 1a; reads on an immunoresponsive cells comprising an NKG2D polypeptide and a fusion polypeptide comprising DAP10 and DAP12). Liu et. al. further teaches that the polypeptide sequence further comprises a chemokine receptor that helps to direct T cells moving towards chemokines expressed by tumors wherein the chemokine receptor is chosen from a group including CXCR2 [0017] (reads on comprising a CXCR2 polypeptide).
Regarding claim 4, Liu et. al. teaches the NKG2D polypeptide comprising full-length human NKG2D polypeptide of SEQ ID NO: 1, which is 99.7% identical to instant SEQ ID NO: 14 as shown below:
RESULT 1
US-16-827-697-1
Query Match 99.7%; Score 1197; DB 1; Length 216;
Best Local Similarity 99.5%;
Matches 215; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 MGWIRGRRSRHSWEMSEFHNYNLDLKKSDFSTRWQKQRCPVVKSKCRENASPFFFCCFIA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MGWIRGRRSRHSWEMSEFHNYNLDLKKSDFSTRWQKQRCPVVKSKCRENASPFFFCCFIA 60
Qy 61 VAMGIRFIIMVAIWSAVFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNW 120
||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VAMGIRFIIMVTIWSAVFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNW 120
Qy 121 YESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 YESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLT 180
Qy 181 IIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV 216
||||||||||||||||||||||||||||||||||||
Db 181 IIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV 216
Regarding claims 5 and 6, SEQ ID NO: 1 varies from SEQ ID NO: 4 at residue 72. As evidenced by U.S. 20180371051, SEQ ID NO: 1 (identical to SEQ ID NO: 1 of Liu et. al.) and SEQ ID NO: 76 (identical to SEQ ID NO: 14) are both known variants of full-length human NKG2D [0059] (reads on functional variant of SEQ ID NO: 14).
Regarding claim 8, Liu et. al. teaches a chimeric version NKG2D polypeptide comprising SEQ ID NO: 2 wherein the human transmembrane domain is substituted for the mouse NKG2D transmembrane domain [0029, 0036, 0044].
Regarding claim 9, the DAP10/12 fusion polypeptide of Liu et. al. is DAP10 fused at the C-terminus to the cytoplasmic domain of DAP12, resulting in N-DAP10-DAP12 intracellular-C (See Fig. 1A, [0009]) (reads on A-B-C-D-E, wherein A, C, and E are optional and B is a DAP10 polypeptide and D is a DAP12 polypeptide).
Regarding claim 10, Liu et. al. teaches the adaptor protein comprising SEQ ID NO: 4, which comprises a variant of instant SEQ ID NO: 1 comprising a one amino acid deletion compared to instant SEQ ID NO: 1 and having 97.8% identity to SEQ ID NO: 1 (reads on at least about 98% identity):
RESULT 1
US-18-551-843-1
Query Match 97.8%; Score 458.5; DB 1; Length 93;
Best Local Similarity 98.9%;
Matches 92; Conservative 0; Mismatches 0; Indels 1; Gaps 1;
Qy 1 MIHLGHILFLLLLPVAAAQTTPGERSSLPAFYPGTSGSCSGCGSLSLPLLAGLVAADAVA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MIHLGHILFLLLLPVAAAQTTPGERSSLPAFYPGTSGSCSGCGSLSLPLLAGLVAADAVA 60
Qy 61 SLLIVGAVFLCARPRRSPAQ-DGKVYINMPGRG 92
|||||||||||||||||||| ||||||||||||
Db 61 SLLIVGAVFLCARPRRSPAQEDGKVYINMPGRG 93
As evidenced by Uniprot Q9UBK5 HSCT_Human, SEQ ID NO: 4 of Liu et. al. is an alternate isoform Q9UBK5-2 which is missing an “E” at amino acid 81.
Regarding claim 14, as shown above, SEQ ID NO: 4 comprises instant SEQ ID NO: 8 (bolded).
Regarding claims 16-19, Liu et. al. teaches that the fusion protein comprises the intracellular domain of DAP12 of SEQ ID NO: 3, which is 100% identical to instant SEQ ID NO: 9. As evidenced by Uniprot O43914 TYOBP_Human, the intracellular domain of DAP12 comprises a polypeptide identical to instant SEQ ID NO: 11 (elected species), residues 62-113 of SEQ ID NO: 9.
Regarding claim 23, as described in the 112(d) above, all proteins comprise both N and C terminal sequences.
Regarding claim 28, the cells of Liu et. al. do not comprise an anti-EpCAM peptide.
Regarding claim 29, as described above, Liu et. al. teaches the fusion protein comprises DAP10 fused to the ICD of CD3 zeta (reads on full-length DAP10) fused to the ICD of DAP12 (Fig. 1a, Fig. 2a, [0009], [0030]). Liu et. al. teaches that the DAP10 adaptor protein is SEQ ID NO: 4 and the DAP12 adaptor protein is SEQ ID NO: 3, which as evidenced by Uniprot O43914 TYOBP_Human is human DAP12, and the intracellular signaling domain is residues 62-113. As evidenced by Uniprot Q9UBK5 HSCT_Human, human DAP10, SEQ ID NO: 4 is a secondary isoform of DAP10 and therefore is full-length human DAP10.
Regarding claim 33, Liu et. al. teaches that the cell is a T-cell or an NK-cell [0002].
Regarding claim 34, Liu et. al. teaches the cells may be a CD8+ or CD4+ T cells [0027].
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 2, 3, and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20200308248 to Liu et. al. published 1 October 2020 and effectively filed 23 March 2020 (IDS dated 9/21/2023) as applied to claim 1 above, and further in view of Jin, Linchun, et al. "CXCR1-or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors." Nature communications 10.1 (2019): 4016, published 5 September 2019 (Of Record, IDS dated 9/21/2023) as evidenced by Uniprot P25025 · CXCR2_HUMAN.
The teachings of Liu et. al. in regard to claim 1 are in the 102 rejection above.
Liu et. al. teaches that the cells are human T cells [0026-0027].
Liu et. al. does not explicitly teach that the CXCR2 polypeptide is human CXCR2. This deficiency is resolved by Jin et. al.
Jin et. al. teaches CAR-T cells with increased trafficking by expressing the IL-8 receptors CXCR1 or CXCR2 (Abstract; Fig. 3). Jin et. al. teaches that the T cells are human T cells (See “Methods: Transduction of human T cells and tumor cells lines” section) and that the construct were made by human CXCR2 (See “Methods: Retroviral and lentiviral constructs” section).
It would have been obvious to a person of ordinary skill in the art, before the effective filing date, to use the human CXCR2 of Jin et. al. a human T cell as taught by both Liu et. al. and Jin et. al. in order to benefit from the improved T cell trafficking to tumors as taught by both Liu et. al. and Jin et. al. This would have a reasonable expectation of success because a person of ordinary skill in the art would expect that using a human CXCR2 protein in a human T-cell would have the disclosed function of improving T-cell trafficking.
Regarding claims 31 and 32, Liu et. al. does not teach that the CXCR2 polypeptide has at least about 85% identity to the sequence of SEQ ID NO: 87, or wherein it has the amino acid sequence of SEQ ID NO: 37.
Liu et. al. further teaches the peptide construct encoded by a polypeptide separated by 2A sites (Fig. 2A). The teachings of Jin et. al. are above. As evidenced by Uniprot P25025 · CXCR2_HUMAN, SEQ ID NO: 37 is the full-length sequence of human CXCR2.
It would have been obvious, to a person of ordinary skill in the art, before the effective filing date, to use the full-length human CXCR2 of Jin et. al. in order to benefit from the improvement of T-cell trafficking to cancer cells as taught by Jin et. al. This would have a reasonable expectation of success because a person of ordinary skill in the art would know that in order to get the full effect of CXCR2 on T-cell trafficking it would be most effective to use expression of the entire CXCR2 protein and Jin et. al. teaches the peptide constructs comprising distinct polypeptides separated by 2A ribosome skipping sites; and therefore a person of ordinary skill in the art would understand the teachings of Liu et. al. to be directed at expression of the full-length human CXCR2 as a separate polypeptide in order to improve trafficking.
Claim(s) 7 is rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20200308248 to Liu et. al. published 1 October 2020 and effectively filed 23 March 2020 (IDS dated 9/21/2023) as applied to claim 1 above, and further in view of Lehner, Manfred, et al. "Redirecting T cells to Ewing's sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection." PloS one 7.2 (2012): e31210 (Of Record, IDS dated 9/21/2023).
The teachings of Liu et. al. in regard to claim 1 are in the 102 rejection above.
Liu et. al. does not teach the immunosuppressive cell comprising a variant NKG2D protein wherein the variant NKG2D protein is truncated.
This deficiency is resolved by Lehner et. al.
Lehner teaches a method of treating Ewing’s Sarcoma which expresses NKG2D ligands comprising using an engineered T-cell comprising an NKG2D chimeric receptor comprising the ectodomain of NKG2D (reads on a truncated NKG2D variant) fused to a CD3-zeta/CD28 derived signaling domain (Abstract, “Generation of chNKG2D” section, Fig. 2). Lehner teaches that ESFT cancer cells are kill by T cells expressing the chNKG2D (Fig. 3). Lehner teaches “Notably, CD28 signaling enhances the resistance to TGF-β1 and regulatory T cells (Tregs) and thus could be particularly relevant in metastasized ESFT, for which secretion of TGF-β1 and increased numbers of infiltrating Tregs have been described [20], [35], [36]. Further, signal amplification by CD28 reduces the threshold of endocytosed receptor molecules required for T cell activation [37], and, hence may be favorable for targeting ESFT, which express NKG2D-Ls often at rather low levels (Fig. 1)”.
It would have been obvious to a person of ordinary skill in the art, before the effective filing date, to substitute the chimeric NKG2D of Lehner et. al. for the wild-type NKG2D of Liu et. al. in the T cells of Liu et. al. in order to benefit from the decreased receptor endocytosis a favorability for targeting ESFT or cancers that express low levels of NKG2D-Ls. This would have a reasonable expectation of success because a person of ordinary skill in the art would expect to achieve cancer targeting using the chimeric NKG2D of Lehner et. al.; costimulation using the DAP10/12 fusion protein of Liu et. al., which would be able to interact with endogenous NKG2D even if it did not interact directly with the chimeric NKG2D; and improved T cell trafficking using CXCR2 as taught by Liu et. al. Both Liu et. al. and Lehner et. al. teach that each of these compositions improve effector cells for targeting cancer, and therefore a person of ordinary skill would be able to combine the different chimeric receptors in order to make an improved effector T or NK cell for targeting cancer.
Claim(s) 23, and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20200308248 to Liu et. al. published 1 October 2020 (IDS dated 9/21/2023) and effectively filed 23 March 2020 as applied to claim 1 above, and further in view of WO2022083590 A1 to Wang et. al. effectively filed 19 October 2020 (citations refer to Google machine translation).
The teachings of Liu et. al. in regard to claim 1 are in the 102 rejection above.
Liu et. al. does not teach the immunosuppressive cell wherein the fusion protein further comprises an additional N- or C-terminal sequence, wherein the sequence is a CD8a leader sequence, a 4-1BB endodomain, or a CD27 endodomain.
Wang et. al. teaches chimeric receptors comprising a DAP12 and a co-stimulatory signal domain (Abstract). Wang et. al. teaches the DAP12 fusion proteins comprising an additional co-stimulatory domain, wherein the preferred co-stimulatory domain is 4-1BB (p. 4, middle). Wang et. al. teaches that in combination with a cancer-targeting chimeric peptide, the DAP12/4-1BB fusion proteins these fusion proteins increase cytotoxicity against target cells in vitro (Fig. 5), increase IFN-gamma release (Fig. 6), and are effective in vivo tumor mouse model at killing tumors (Example 4, Fig. 8).
It would have been obvious to a person of ordinary skill in the art, before the effective filing date, to fuse the 4-1BB endodomain to the end of the fusion protein of Liu et. al., resulting in a DAP10-DAP12 ICD-4-1BB ICD fusion molecule in order to benefit from the combined costimulatory signaling of DAP12 and 4-1BB together for improved cancer targeting and co-stimulatory activation for effector cells. This would have a predictable effect because Liu et. al. teaches DAP10/DAP12 fusion proteins comprising the ICD of DAP12 for increased effector cell activation and co-stimulation and Wang et. al. teaches combinations of the DAP12 and 4-1BB intracellular domains for effector cell-stimulation. Therefore, a person of ordinary skill in the art would have a reasonable expectation of effective co-stimulation from a combined fusion protein.
Claim(s) 27 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20200308248 to Liu et. al. published 1 October 2020 and effectively filed 23 March 2020 as applied to claim 1 above, and further in view of WO2020168298 A2 to Epstein et. al. published 20 August 2020 (IDS dated 9/21/2023) and Wu et al. 1999 (Science, 2S(5428), 730-732) (IDS dated 10/14/2025) as evidenced by “Homo sapiens membrane protein DAP10 (DAP10) mRNA” GenBank Accession numbers AF122904 (IDS dated 10/14/2025) and AF072844 (IDS dated 10/14/2025).
The teachings of Liu et. al. in regard to claim 1 are in the 102 rejection above.
Liu et. al. does not teach the immunosuppressive cell wherein the fusion protein has the sequence of SEQ ID NO: 60. The Examiner interprets “has” in this case to mean “comprising” SEQ ID NO: 60.
The differences between the DAP10/12 fusion protein of Liu et. al. and instant SEQ ID NO: 60 are that 1) Liu et. al. teaches the DAP10/12 fusion protein comprises a GS linker (Fig. 2a) and 2) Liu et. al. teaches a DAP10 sequence that varies at a single amino acid position 81 as described in the 102 above.
This deficiency is partially resolved by Epstein.
Epstein et. al. teaches CAR polypeptides comprising an anti-Lym1 antigen binding domain and an intracellular DAP10/DAP12 fusion signaling domain comprising the intracellular signaling domain of DAP10 fused at the C terminus with the intracellular signaling domain of DAP12, wherein the framework of the DAP CAR comprises SEQ ID NO: 29, which is nearly identical to instant SEQ ID NO: 60 residues 70-145 except for a missing E residue in the DAP10 sequence as shown:
Qy 2 TTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLL 61
||| | | | | |: | : : : | | | |
Db 20 TTPGERSSLP--------------AFYPGTSGSCSGCG---SLSLPLLAGLVAADAVASL 62
Qy 62 SLVITLYCLCARPRRSPAQ-DGKVYINMPGRGYFLGRLVPRGRGAAEAATRKQRITETES 120
|:: ||||||||||| ||||||||||||||||||||||||||||||||||||||||
Db 63 -LIVGAVFLCARPRRSPAQEDGKVYINMPGRGYFLGRLVPRGRGAAEAATRKQRITETES 121
Qy 121 PYQELQGQRSDVYSDLNTQRPYYK 144
||||||||||||||||||||||||
Db 122 PYQELQGQRSDVYSDLNTQRPYYK 145
Epstein et. al. teaches that the DAP CAR activates T-cells and to target cancer in vitro and in vivo (See, for example Figs. 24-25, Experiment No. 2).
It would have been obvious to one of ordinary skill in the art at the time of filing to make an alternate DAP10/DAP12 fusion protein of Liu et. al. lacking a G4S linker because it was common in the art to make fusion proteins with and without linkers. This would have a reasonable expectation of success because Epstein et. al. teaches that a linker between the DAP10 intracellular domain and the DAP12 intracellular domain in a fusion protein is not required for effective T-cell activation signaling in a DAP10/DAP12 fusion.
This deficiency is partially resolved by Wu.
Wu teaches that DAP10 is alternatively expressed as two splice variants (Fig. 1), corresponding to GenBank Accession numbers AF122904 and AF072844, which encode polypeptides differing at a single amino acid position in the C-terminal tail (see alignment below).
AF122904 1 MIHLGHILFLLLLPVAAAQTTPGERSSLPAFYPGTSGSCSGCGSLSLPLLAGLVAADAVA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
AF072844 41 MIHLGHILFLLLLPVAAAQTTPGERSSLPAFYPGTSGSCSGCGSLSLPLLAGLVAADAVA 60
AF122904 61 SLLIVGAVFLCARPRRSPAQEDGKVYINMPGRG 93
|||||||||||||||||||| ||||||||||||
AF072844 61 SLLIVGAVFLCARPRRSPAQ-DGKVYINMPGRG 92
It would have been obvious to one of ordinary skill in the art that the DAP10 sequence DAP10/DAP12 fusion protein of Liu could alternatively comprise amino acids 70-93 of instant SEQ ID NO: 1, which corresponds to the C terminal domain of the DAP10 splice variant AF122904 taught by Wu. The skilled artisan would have recognized that sequences from two naturally occurring splice variants of the same protein, absent any known functional differences between said isoforms, would constitute simple substitution of one known element for another to obtain predictable results (See MPEP §2143).
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.
Copending Application No. 17762657
Claims 1, 4-10, 14, 16-19, 23, 27-30, and 33-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2, 53-55, 57, 59, 61-63 of copending Application No. 17762657 in view of U.S. 20200308248 to Liu et. al. published 1 October 2020 and effectively filed 23 March 2020.
This is a provisional nonstatutory double patenting rejection.
Claim 2 of ‘657 teaches a fusion polypeptide having the formula from N-to -C terminus comprising an optional N terminal sequence, a DAP10 polypeptide having the amino acid sequence of SEQ ID NO: 1 (identical to instant SEQ ID NO: 1), or a truncated fragment thereof having SEQ ID NO: 2, an optional linker sequence, and a DAP12 polypeptide having the amino acid sequence of SEQ ID NO: 11; wherein the fusion polypeptide comprises SEQ ID NO: 60 (claim 53; identical to instant SEQ ID NO: 60), wherein the fusion polypeptide does not comprise an anti-EpCAM peptide (claim 54). Claim 55 teaches wherein the fusion polypeptide further comprises an NKG2D polypeptide wherein the NKG2D polypeptide is linked with a P2A linker or a furin cleavage site and P2A linker; wherein NKG2D is full-length comprising SEQ ID NO: 14 (identical to instant SEQ ID NO: 14) or a truncated fragment thereof having an amino acid sequence of SEQ ID NO: 17.
Thus, the difference between the claims of ‘657 and the instant claims is that ‘657 does not teach the immunoresponsive cell comprising the polypeptide and does not teach that the immunoresponsive cell further comprises a CXCR2 polypeptide.
This deficiency is resolved by Liu et. al.
The teachings of Liu et. al. are in the 102 rejection above. Briefly, Liu et. al. teaches T cells and NK cells comprising a DAP10/12 fusion polypeptide comprising DAP10 fused to the ICD of DAP12 and NKG2D, wherein the fusion protein further comprises CXCR2 to promote T-cell trafficking to a tumor.
It would have been obvious as of the effective filing date to combine the fusion polypeptide of the ‘657 claims with the fusion protein of Liu et. al. in a T cell or NK cell as taught by Liu et. al. in order to benefit from the increased T-cell trafficking from CXCR2 in a T-cell comprising NKG2D and a DAP10/12 fusion protein as taught by Liu et. al. This would have a reasonable expectation of success because Liu et. al. teaches the same NKG2D and DAP10/12 as the ‘657 claims and a person of ordinary skill would expect to be able to make a T cell comprising the polypeptides as claimed in order to benefit from disclosed use of the T cell to treat cancer expressing NKG2D ligands as taught by Liu.
Claim(s) 2, 3, and 31-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2, 53-55, 57, 59, 61-63 of copending Application No. 17762657 in view of U.S. 20200308248 to Liu et. al. published 1 October 2020 and effectively filed 23 March 2020 as applied to claim 1 above, and further in view of Jin, Linchun, et al. "CXCR1-or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors." Nature communications 10.1 (2019): 4016, published 5 September 2019 (Of Record, IDS dated 9/21/2023) as evidenced by Uniprot P25025 · CXCR2_HUMAN.
The teachings of ‘657 in view of Liu et. al. in regard to claim 1 are in the NSDP rejection above.
‘657 modified by Liu et. al. teaches that the cells are human T cells [0026-0027].
Modified ‘657 does not explicitly teach that the CXCR2 polypeptide is human CXCR2. This deficiency is resolved by Jin et. al.
Jin et. al. teaches CAR-T cells with increased trafficking by expressing the IL-8 receptors CXCR1 or CXCR2 (Abstract; Fig. 3). Jin et. al. teaches that the T cells are human T cells (See “Methods: Transduction of human T cells and tumor cells lines” section) and that the construct were made by human CXCR2 (See “Methods: Retroviral and lentiviral constructs” section).
It would have been obvious to a person of ordinary skill in the art, before the effective filing date, to use the human CXCR2 of Jin et. al. a human T cell as taught by both Liu et. al. and Jin et. al. in order to benefit from the improved T cell trafficking to tumors as taught by both Liu et. al. and Jin et. al. This would have a reasonable expectation of success because a person of ordinary skill in the art would expect that using a human CXCR2 protein in a human T-cell would have the disclosed function of improving T-cell trafficking.
Regarding claims 31 and 32, modified ‘657 does not teach that the CXCR2 polypeptide has at least about 85% identity to the sequence of SEQ ID NO: 87, or wherein it has the amino acid sequence of SEQ ID NO: 87.
Liu et. al. further teaches the peptide construct encoded by a polypeptide separated by 2A sites (Fig. 2A). The teachings of Jin et. al. are above. As evidenced by Uniprot P25025 · CXCR2_HUMAN, SEQ ID NO: 87 is the full-length sequence of SEQ ID NO: 87.
It would have been obvious, to a person of ordinary skill in the art, before the effective filing date, to use the full-length human CXCR2 of Jin et. al. in order to benefit from the improvement of T-cell trafficking to cancer cells as taught by Jin et. al. This would have a reasonable expectation of success because a person of ordinary skill in the art would know that in order to get the full effect of CXCR2 on T-cell trafficking it would be most effective to use expression of the entire CXCR2 protein and Jin et. al. teaches the peptide constructs comprising distinct polypeptides separated by 2A ribosome skipping sites; and therefore a person of ordinary skill in the art would understand the teachings of Liu et. al. to be directed at expression of the full-length human CXCR2 as a separate polypeptide in order to improve trafficking.
Claim(s) 23, and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2, 53-55, 57, 59, 61-63 of copending Application No. 17762657 in view of U.S. 20200308248 to Liu et. al. published 1 October 2020 and effectively filed 23 March 2020 as applied to claim 1 above, and further in view of WO2022083590 A1 to Wang et. al. effectively filed 19 October 2020 (citations refer to Google machine translation).
The teachings of ‘657 in view of Liu et. al. in regard to claim 1 are in the NSDP rejection above.
‘657 in view of Liu et. al. does not teach the immunosuppressive cell wherein the fusion protein further comprises an additional N- or C-terminal sequence, wherein the sequence is a CD8a leader sequence, a 4-1BB endodomain, or a CD27 endodomain.
Wang et. al. teaches chimeric receptors comprising a DAP12 and a co-stimulatory signal domain (Abstract). Wang et. al. teaches the DAP12 fusion proteins comprising an additional co-stimulatory domain, wherein the preferred co-stimulatory domain is 4-1BB (p. 4, middle). Wang et. al. teaches that in combination with a cancer-targeting chimeric peptide, the DAP12/4-1BB fusion proteins these fusion proteins increase cytotoxicity against target cells in vitro (Fig. 5), increase IFN-gamma release (Fig. 6), and are effective in vivo tumor mouse model at killing tumors (Example 4, Fig. 8).
It would have been obvious to a person of ordinary skill in the art, before the effective filing date, to fuse the 4-1BB endodomain to the end of the fusion protein of ‘657 resulting in a DAP10-DAP12 ICD-4-1BB ICD fusion molecule in order to benefit from the combined costimulatory signaling of DAP12 and 4-1BB together for improved cancer targeting and co-stimulatory activation for effector cells. This would have a predictable effect because ‘657 in view of Liu et. al. teaches DAP10/DAP12 fusion proteins comprising the ICD of DAP12 for increased effector cell activation and co-stimulation and Wang et. al. teaches combinations of the DAP12 and 4-1BB intracellular domains for effector cell-stimulation. Therefore, a person of ordinary skill in the art would have a reasonable expectation of effective co-stimulation from a combined fusion protein.
Copending Application No. 17927132
Claims 1, 4-10, 14, 16-19, 23, 27-30, and 33-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 8-9, 11-14, 16, 21-22, 37, 50-52, 58, 62, 64, 66, 68-69, and 75 of copending Application No. 17927132 in view of U.S. 20200308248 to Liu et. al. published 1 October 2020 and effectively filed 23 March 2020.
This is a provisional nonstatutory double patenting rejection.
Claim 1 of ‘132 teaches an immunoresponsive cell comprising a chimeric NKG2D protein, wherein the immunoresponsive cell is a T-cell, an NK cell, macrophage or neutrophil and the chimeric NKG2D protein comprises a human NKG2D extracellular domain or a variant thereof and a murine NKG2D transmembrane domain or a variant thereof. Claims 3, 8, 9, 11, are directed towards the sequences of the chimeric NKG2D protein including the SEQ ID NOs: 7, 8, and 10, which are all truncations of instant SEQ ID NO: 14 lacking the N-terminal intracellular sequences. Claims 22, 37, and 50 teach wherein the cell comprises a DAP12 polypeptide or variant, a DAP10 polypeptide or variant, and a DAP12 fused to a DAP10.
Thus, the difference between the claims of ‘132 and the instant claims is that ‘132 claims do not explicitly teach the DAP10 and DAP12 fusion comprises full-length DAP10 fused to the intracellular signaling domain of DAP12 or the particular sequences (e.g. variants of SEQ ID NOs: 1 and 9) and does not teach that the immunoresponsive cell further comprises a CXCR2 polypeptide.
This deficiency is resolved by Liu et. al.
The teachings of Liu et. al. are in the 102 rejection above. Briefly, Liu et. al. teaches T cells and NK cells comprising a DAP10/12 fusion polypeptide comprising DAP10 fused to the ICD of DAP12 and NKG2D, wherein the fusion protein further comprises CXCR2 to promote T-cell trafficking to a tumor. Liu et. al. teaches the full-length DAP10 and DAP12 sequences of SEQ ID NOs: 3 and 4 as described in the 102 above.
It would have been obvious as of the effective filing date to combine immunoresponsive cell comprising a chimeric NKG2D and a DAP10/12 fusion protein of the ‘132 claims with the NK and T cells comprising an NKG2D and DAP10/12 fusion protein of Liu et. al. in a T cell or NK cell as taught by Liu et. al. in order to benefit from 1) the NKG2D protein variants as taught by the claims of ‘132 and 2) the increased T-cell trafficking from CXCR2 in a T-cell comprising NKG2D and a DAP10/12 fusion protein as taught by Liu et. al. This would have a reasonable expectation of success because Liu et. al. teaches NKG2D and DAP10/12 and the ‘132 claims teach NKG2D variant and DAP10/12 fusion proteins and a person of ordinary skill would expect to be able to make a T cell comprising the polypeptides as claimed in order to benefit from disclosed use of the T cells to treat cancer expressing NKG2D ligands as taught by Liu and the improved NKG2D polypeptide as taught by ‘132.
Claim(s) 2, 3, and 31-32 are 1, 3, 8-9, 11-14, 16, 21-22, 37, 50-52, 58, 62, 64, 66, 68-69, and 75 of copending Application No. 17927132 in view of U.S. 20200308248 to Liu et. al. published 1 October 2020 and effectively filed 23 March 2020 as applied to claim 1 above, and further in view of Jin, Linchun, et al. "CXCR1-or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors." Nature communications 10.1 (2019): 4016, published 5 September 2019 (Of Record, IDS dated 9/21/2023) as evidenced by Uniprot P25025 · CXCR2_HUMAN.
The teachings of ‘132 in view of Liu et. al. in regard to claim 1 are in the NSDP rejection above.
‘132 modified by Liu et. al. teaches that the cells are human T cells [0026-0027].
Modified ‘132 does not explicitly teach that the CXCR2 polypeptide is human CXCR2. This deficiency is resolved by Jin et. al.
Jin et. al. teaches CAR-T cells with increased trafficking by expressing the IL-8 receptors CXCR1 or CXCR2 (Abstract; Fig. 3). Jin et. al. teaches that the T cells are human T cells (See “Methods: Transduction of human T cells and tumor cells lines” section) and that the construct were made by human CXCR2 (See “Methods: Retroviral and lentiviral constructs” section).
It would have been obvious to a person of ordinary skill in the art, before the effective filing date, to use the human CXCR2 of Jin et. al. a human T cell as taught by both Liu et. al. and Jin et. al. in order to benefit from the improved T cell trafficking to tumors as taught by both Liu et. al. and Jin et. al. This would have a reasonable expectation of success because a person of ordinary skill in the art would expect that using a human CXCR2 protein in a human T-cell would have the disclosed function of improving T-cell trafficking.
Regarding claims 31 and 32, modified ‘132 does not teach that the CXCR2 polypeptide has at least about 85% identity to the sequence of SEQ ID NO: 87, or wherein it has the amino acid sequence of SEQ ID NO: 87.
Liu et. al. further teaches the peptide construct encoded by a polypeptide separated by 2A sites (Fig. 2A). The teachings of Jin et. al. are above. As evidenced by Uniprot P25025 · CXCR2_HUMAN, SEQ ID NO: 87 is the full-length sequence of SEQ ID NO: 87.
It would have been obvious, to a person of ordinary skill in the art, before the effective filing date, to use the full-length human CXCR2 of Jin et. al. in order to benefit from the improvement of T-cell trafficking to cancer cells as taught by Jin et. al. This would have a reasonable expectation of success because a person of ordinary skill in the art would know that in order to get the full effect of CXCR2 on T-cell trafficking it would be most effective to use expression of the entire CXCR2 protein and Jin et. al. teaches the peptide constructs comprising distinct polypeptides separated by 2A ribosome skipping sites; and therefore, a person of ordinary skill in the art would understand the teachings of Liu et. al. to be directed at expression of the full-length human CXCR2 as a separate polypeptide to improve trafficking.
Claim(s) 23, and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 8-9, 11-14, 16, 21-22, 37, 50-52, 58, 62, 64, 66, 68-69, and 75 of copending Application No. 17927132 in view of U.S. 20200308248 to Liu et. al. published 1 October 2020 and effectively filed 23 March 2020 as applied to claim 1 above, and further in view of WO2022083590 A1 to Wang et. al. effectively filed 19 October 2020 (citations refer to Google machine translation).
The teachings of ‘132 in view of Liu et. al. in regard to claim 1 are in the NSDP rejection above.
‘132 in view of Liu et. al. does not teach the immunosuppressive cell wherein the fusion protein further comprises an additional N- or C-terminal sequence, wherein the sequence is a CD8a leader sequence, a 4-1BB endodomain, or a CD27 endodomain.
Wang et. al. teaches chimeric receptors comprising a DAP12 and a co-stimulatory signal domain (Abstract). Wang et. al. teaches the DAP12 fusion proteins comprising an additional co-stimulatory domain, wherein the preferred co-stimulatory domain is 4-1BB (p. 4, middle). Wang et. al. teaches that in combination with a cancer-targeting chimeric peptide, the DAP12/4-1BB fusion proteins these fusion proteins increase cytotoxicity against target cells in vitro (Fig. 5), increase IFN-gamma release (Fig. 6), and are effective in vivo tumor mouse model at killing tumors (Example 4, Fig. 8).
It would have been obvious to a person of ordinary skill in the art, before the effective filing date, to fuse the 4-1BB endodomain to the end of the fusion protein of ‘132 resulting in a DAP10-DAP12 ICD-4-1BB ICD fusion molecule in order to benefit from the combined costimulatory signaling of DAP12 and 4-1BB together for improved cancer targeting and co-stimulatory activation for effector cells. This would have a predictable effect because ‘132 in view of Liu et. al. teaches DAP10/DAP12 fusion proteins comprising the ICD of DAP12 for increased effector cell activation and co-stimulation and Wang et. al. teaches combinations of the DAP12 and 4-1BB intracellular domains for effector cell-stimulation. Therefore, a person of ordinary skill in the art would have a reasonable expectation of effective co-stimulation from a combined fusion protein.
Copending Application No. 19115718
Claims 1, 4-10, 14, 16-19, 23, 27-30, and 33-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-48 of copending Application No. 19115718.
This is a provisional nonstatutory double patenting rejection.
The claims of ‘718 teach a method of making an immunoresponsive cell comprising an NKG2D polypeptide, wherein the cell has been genetically modified to express an NKG2D polypeptide; claim 3 teaches wherein the cell is genetically modified to further express a DAP10/12 fusion polypeptide; claim 4 teaches the method of claim 3, wherein the fusion polypeptide has the formula from N-to-C terminus A-B-C-D-E wherein A is an optional N terminal sequence, B is a DAP10 polypeptide, C is an optional linker, D is a DAP12 polypeptide, and E is an optional C-terminal sequence. Claim 5 teaches the DAP10 has at least about 80% identity to SEQ ID NO: 1 (identical to instant SEQ ID NO: 1); wherein the DAP12 polypeptide comprises a functional variant which is a truncated version of SEQ ID NO: 9 (identical to instant SEQ ID NO: 9) (claim 10); wherein the truncated version comprises amino acids 22-113 of SEQ ID NO: 9 (claim 11); wherein the DAP12 polypeptide comprises any one of SEQ ID Nos: 9-13, wherein SEQ ID NO: 11 is identical to instant SEQ ID NO: 11 (claim 12). Claim 15 teaches wherein the fusion polypeptide comprises SEQ ID NO: 60 to 63 (wherein SEQ ID NO: 60 is identical to instant SEQ ID NO: 60). Claim 16 teaches NKG2D is a mammalian polypeptide, optionally a human polypeptide; claim 17 teaches the NKG2D is a functional variant of SEQ ID NO: 14 (identical to instant SEQ ID NO: 14); claim 18 teaches the NKG2D is a chimeric polypeptide. Claim 20 teaches the method wherein the immune cell is genetically modified to express a CXCR2 polypeptide; claim 21 teaches that the CXCR2 is mammalian, optionally human. Claim 23 teaches CXCR2 comprises SEQ ID NO: 87, 100% identical to instant SEQ ID NO: 87. Claim 29 teaches that the cell is a T-cell or an NK cell; claims 30 and 31 recite the immune cells are alpha-beta T cells, gamma-delta T cells, or CD4+ T cells.
Claim 33 recites an immunoresponsive cells obtainable by the method of any of the previous claims. Claim 35 recites wherein the immunoresponsive cell is genetically modified to expression a DAP10 and DAP12 fusion polypeptide. Claim 36 recites the immunoresponsive cell further expressing a CXCR2 polypeptide. Claim 37 recites the cell is a T-cell or NK-cell. Claims 39-40 claim a population of T cells with a particular CD4:CD8 ratio, which anticipates CD4+ or CD8+ T cells.
Thus, the claimed method of making the instant composition and the immunoresponsive cells made by the method of making of ‘718 anticipate the instantly claimed immunoresponsive cells.
Claim(s) 23, and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-48 of copending Application No. 19115718 as applied to claim 1 above, and further in view of WO2022083590 A1 to Wang et. al. effectively filed 19 October 2020 (citations refer to Google machine translation).
The teachings of ‘718 in regard to claim 1 are in the NSDP rejection above.
‘718 in view of Liu et. al. does not teach the immunosuppressive cell wherein the fusion protein further comprises an additional N- or C-terminal sequence, wherein the sequence is a CD8a leader sequence, a 4-1BB endodomain, or a CD27 endodomain.
Wang et. al. teaches chimeric receptors comprising a DAP12 and a co-stimulatory signal domain (Abstract). Wang et. al. teaches the DAP12 fusion proteins comprising an additional co-stimulatory domain, wherein the preferred co-stimulatory domain is 4-1BB (p. 4, middle). Wang et. al. teaches that in combination with a cancer-targeting chimeric peptide, the DAP12/4-1BB fusion proteins these fusion proteins increase cytotoxicity against target cells in vitro (Fig. 5), increase IFN-gamma release (Fig. 6), and are effective in vivo tumor mouse model at killing tumors (Example 4, Fig. 8).
It would have been obvious to a person of ordinary skill in the art, before the effective filing date, to fuse the 4-1BB endodomain to the end of the fusion protein of ‘718 resulting in a DAP10-DAP12 ICD-4-1BB ICD fusion molecule in order to benefit from the combined costimulatory signaling of DAP12 and 4-1BB together for improved cancer targeting and co-stimulatory activation for effector cells. This would have a predictable effect because ‘718 teaches DAP10/DAP12 fusion proteins comprising the ICD of DAP12 for increased effector cell activation and co-stimulation and Wang et. al. teaches combinations of the DAP12 and 4-1BB intracellular domains for effector cell-stimulation. Therefore, a person of ordinary skill in the art would have a reasonable expectation of effective co-stimulation from a combined fusion protein.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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