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 .
Application Status
Claims 1-2, 20-21, 28-29, 47-49, and 55-60 are pending and examined on the merits herein.
Power of Attorney
It is noted that a Power of Attorney is not on record for the instant application. The Applicant is encouraged to file a Power of Attorney in the event that the Examiner needs to communicate with an authorized representative for the Applicant during the prosecution of the case.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 71-75. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 20 and 47 are objected to because of the following informalities:
Regarding claim 20, Line 1 recites “polynucleotide or and/ or” please delete the first “or”;
Regarding claim 47, the second to last line has duplicate recitation of “and” please delete one of the recitations;
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 2, 29, 49, 55, 57, and 60 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, because 35 U.S.C. 112(b) and 35 U.S.C. 112 (pre-AIA ), second paragraph, require claims to particularly point-out and distinctly claim subject matter.
Regarding claim 2, the instant claim recites extracellular domain mutations as shown in figure 2. It attempts to incorporate by reference to a figure; however, such incorporation is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. In the instant case, there is a practical way to define the invention in words. Incorporation by reference is a necessity doctrine, not for applicant' s convenience. See MPEP 2173.05(s).
Regarding claims 29, 49, 55, and 57, the phrase "e.g." is exemplary language and renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 60, the phrase "optionally" used as exemplary language as it used not as an alternative limitation but in the format of: genus, optionally species. Therefore, the species following the term “optionally” are examples of the members of the genus. This is exemplary language and renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
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.
Claims 1-2, 20-21 and 28-29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hermann (J Biol Chem. 2014 Jan 10;289(2):765-77; IDS entered 03/06/2025).
Regarding claims 1 and 20-21, Hermann teaches that the C terminus of the NKp30 ectodomain variants was fused to a tobacco etch virus (TEV) cleavage site (GS-ENLYFQ-GGS; the glycine-serine linker-flanked TEV cleavage site is underlined) followed by a decahistidine tag and that both constructs encoding 30Stalk-His and 30LBD-His proteins were generated by de novo gene synthesis and cloned into the pFastBac1 vector (page 766, col 2, para 4). Hermann further teaches that both NKp30 variants bound specifically and dose dependently to B7-H6-Ig with very low equilibrium binding constants (KD values) of 5 ± 3 nM and 29 ± 1 nM for the 30Stalk-His and the 30LBD-His proteins, respectively which is surprisingly, these apparent binding affinities are higher than those published for the monovalent NKp30 ectodomain proteins (page 772, col 1, para 2).
Regarding claim 2, Hermann teaches we generated a construct comprising the globular Ig domain (30LBD-His, amino acids 19 –128; Fig. 2A) (page 768, col 2, para 2). This construct includes a detectable label.
Regarding claims 28-29, Hermann teaches insect cells were transfected with recombinant bacmids (page 766, col 2, para 4).
Claims 1-2, 20-21, 28-29, 47-49, 55-56, and 60 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Swanson (US 2018/0256644 A1; PTO-892).
Regarding claim 1, Swanson teaches a transmembrane immunomodulatory protein (TIP) comprising: (i) an ectodomain comprising at least one non-immunoglobulin affinity-modified immunoglobulin superfamily (IgSF) domain comprising one or more amino acid substitution(s) in a wild-type IgSF domain, wherein the at least one affinity-modified IgSF domain specifically binds at least one cell surface cognate binding partner of the wild-type IgSF domain; and (ii) a transmembrane domain (claim 1), wherein the at least one affinity modified IgSF domain has increased binding affinity to the at least one cell surface cognate binding partner compared with the reference wild-type IgSF domain (claim 5), wherein the wild-type IgSF domain is from an IgSF member selected from Nkp30 (claim 10), wherein the wild-type IgSF domain is a human IgSF member (claim 11), the transmembrane immunomodulatory protein of any of claims 1-11, wherein the at least one affinity modified IgSF domain has at least 90% sequence identity to a wild-type IgSF domain or a specific binding fragment thereof contained in the sequence of amino acids set forth in any of SEQ ID NOS: 1-27 (claim 12)
Regarding claim 2, Swanson teaches in some embodiments, the protein is conjugated to a small molecule moiety such as a drug or detectable label (para 0070).
Regarding claim 20, Swanson teaches a recombinant nucleic acid encoding a transmembrane immunomodulatory proteins of any of claims 1-60 (claim 61).
Regarding claim 21, Swanson teaches wherein the transmembrane immunomodulatory protein further comprises an endodomain or cytoplasmic signaling domains (claim 43), wherein the endodomain comprises at least one ITAM (immunoreceptor tyrosine-based activation motif)-containing signaling domain (claim 45), wherein the endodomain comprises a CD3-zeta signaling domain (claim 46).
Regarding claim 28, Swanson teaches an engineered cell comprising the transmembrane immunomodulatory protein of any of claims 1-60 (claim 67), wherein the cell is an immune cell (claim 68).
Regarding claim 29, Swanson teaches wherein the cell is a lymphocyte (claim 69), wherein the lymphocyte is a T cell, a B cell or an NK cell (claim 70).
Regarding claim 47, Swanson teaches a pharmaceutical composition comprising the cell of any of claims 67-74 and a pharmaceutically acceptable carrier (claim 75).
Regarding claim 48, Swanson teaches A method of modulating an immune response in a mammalian subject, comprising administering a cell of any of claims 67-74 or a pharmaceutical composition of claim 75 or claim 76 to the subject (claim 77), wherein modulating the immune response treats a disease or disorder in the subject (claim 78).
Regarding claim 49, Swanson teaches wherein the disease or disorder is a cancer (claim 81), wherein the disease or disorder is melanoma, lung cancer, bladder cancer, or a hematological malignancy (claim 82).
Regarding claim 55, Swanson teaches an affinity modified IgSF domain can be created by site-directed mutagenesis of a wild-type IgSF domain (para 0050) and in some embodiments, the affinity modified IgSF domain of the ectodomain contains one or more amino acid substitutions (alternatively, “mutations” or “replacements”) relative to a wild-type or unmodified polypeptide or a portion thereof containing an immunoglobulin superfamily (IgSF) domain (para 0121). Example 5 describes the high throughput expression and purification of Fc-fusion proteins containing variant ECD Nkp30 (para 0405), wherein the at least one affinity modified IgSF domain has increased binding affinity to the at least one cell surface cognate binding partner compared with the reference wild-type IgSF domain (claim 5) and table 7 with exemplary variant NKp30 polypeptide mutations. Swanson further teaches wherein the at least one affinity-modified IgSF domain specifically binds to a cell surface cognate binding partner that is a tumor specific antigen (claim 35), wherein the tumor specific antigen is B7-H6 (claim 36).
Regarding claim 56, Swanson teaches wherein the affinity-modified IgSF domain is an affinity modified Nkp30 IgSF domain (claim 37).
Regarding claim 60, Swanson teaches in some embodiments, a pharmaceutical composition of the invention can also be used to inhibit growth of mammalian, particularly human, cancer cells as a monotherapy (i.e., as a single agent), in combination with at least one chemotherapeutic agent (i.e., a combination therapy), in combination with a cancer vaccine, in combination with an immune checkpoint inhibitor and/or in combination with radiation therapy (para 0212).
Claim Rejections - 35 USC § 103
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.
Claims 57-59 are rejected under 35 U.S.C. 103 as being unpatentable over Swanson (US 2018/0256644 A1; PTO-892) as applied to claims 1-2, 20-21, 28-29, 47-49, 55-56, and 60 above, and further in view of Semeraro (Sci. Transl. Med.7, 283ra55-283ra55 (2015); PTO-892).
The teachings of Swanson regarding claims 1-2, 20-21, 28-29, 47-49, 55-56, and 60 are detailed above.
Swanson does not teach a method of treatment comprising measuring B7H6 on the cells of the biological sample.
Regarding claims 57 and 59, Semeraro teaches measurement of serum level of B7-H6 in neuroblastoma (NB) patients that correlates with down-regulation of NKp30, bone marrow metastases, chemoresistance, tumor load, and inhibited NK cell functions in vitro (abstract). Semeraro further teaches that the concentration of soluble B7-H6 in the serum may be clinically useful as biomarkers for risk stratification (abstract). Semeraro further teaches that NKp46 and NKp30 have been identified as activating receptors involved in the recognition of NB (page 1, col 2, para 2) and that NKp30/NCR3 is the most NK-specific receptor (page 1, col 2, para 3). Semeraro further teaches that high concentrations of sB7-H6 were found in the serum of some patients with metastatic disease and were associated with an abnormally low NKp30 expression on CD3−CD56dim NK cells and further that sB7-H6 serum concentration was associated with NB dissemination and tumor progression despite therapy (page 3, para 2- page 4 para 1). Semeraro further that NKp30C induces IL-10 release that further enhances B7-H6 transcription and NKp30 signaling, in a vicious feedback loop, culminating inNKp30 down-regulation and tumor escape, conversely, by inducing IFNg, NKp30A and NKp30B might limit the constant exposure of NKp30 to its ligand and prevent NKp30 exhaustion (page 6, col 2, para 2). Semeraro further teaches that at late stages of tumor escape, the NKp30/B7-H6 dialogue is disabled, reflecting and/or participating in immunosubversion (page 9, col 1, para 1). Semeraro further teaches that future therapies of HR-NB might include specific methods to overcome local immunosuppression by myeloid-derived suppressor cells through epigenetic manipulations aimed at restoring the preferential expression of stimulatory NKp30 isoforms (page 9, col 2, para 1).
Regarding claim 58, Semeraro teaches relative serum concentrations of B7-H6 with a mean that is >1.2 increased in metastatic patients (Fig 2E-G).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to measure the level of B7-H6 in a cancer patient and use overexpression of B7-H6 to determine the patient needs treatment as taught by Semeraro in the method of treating cancer using a variant NKp30 with higher affinity for B7-H6 as taught by Swanson. The ordinary artisan would have been motivated to do so because Semeraro teaches measurement of serum level of B7-H6 in neuroblastoma (NB) patients that correlates with down-regulation of NKp30, bone marrow metastases, chemoresistance, tumor load, and inhibited NK cell functions and that treatment would be beneficial to overcome local immunosuppression by through epigenetic to restore stimulatory NKp30. Therefore the ordinary artisan has a reasonable expectation of success to measure serum levels of B7-H6 in a cancer patient, determine that the level is elevated relative to control and administer the high affinity NKp30 variant to restore immune activation.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643
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