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 requirement filed 29 July 2025 is acknowledged. Applicant elects Group I, claims 1-4, 7-27, 34 (partially), 35, 38 (partially), 44-46, 59-66, and 68-72 drawn to a blocking chimeric antigen receptor comprising an extracellular domain more than about 20nm in length comprising
An extracellular domain that is more than about 20nm in length comprising:
A single-chain binding domain
A rigid elongation domain, and
A protease cleavage site capable of being cleaved by a protease;
A transmembrane domain; and
An intracellular domain comprising a full or partial intracellular domain of a membrane phosphatase capable of dephosphorylating phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs),
wherein the protease cleavage site is linked to the intracellular domain by the transmembrane domain,
wherein the binding domain specifically binds to a cell surface epitope present on normal mammalian tissue, but absent on related abnormal mammalian tissue being targeted by an autoimmune response; and polynucleotides encoding the bCAR; and regulatory or effector immune cells comprising the polynucleotide. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 29-33, 34 (partially), 36-37, and 38 (partially) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 considered to be made without traverse in the reply filed on 29 July 2025.
Applicant further elects the species of (i) the protease ADAM and protease cleavage target sites thereof; (ii) an elongation claim of an Ig domain; and (iii) an extracellular or transmembrane domain of CD2. Regarding (i), claims 1, 4, 7-10, 12-22, 24, 34, 35, 38, 44, and 59-66, 68, 70, and 72 are generic to the protease and cleavage site; (ii), claims 1-4, 7-9, 23-24, 34 (partially), 38 (partially), 44-46, and 59-65 are generic to the elongation domain; and (iii) claims are generic 1-4, 7-27, 34 (partially), 35, 38 (partially), 44-46, 59-66, and 68-72
Applicant suggests the species elections reads on claims 1-4, 7-10, 12-21, 23-24, 34, 35, 38, 44-46, 59-66 and 68-72; however, claims 13-21 are dependent on claim 11 and therefore require the non-elected species of elongation domain; claims 66, 68, and 69-72 also require non-elected species of elongation domains. The elections therefore read on claims 1-4, 7-10, 12, 14, 23-24, 34, 35, 38, 44-46, and 59-65.
Claims 11, 13, 15-22, 25, 26, 27, 66, 68, 69, 70, 71, and 72
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 considered to be made without traverse in the reply filed on 29 July 2025, as described above.
Claim Status
Claims 1-4, 7-27, 29-38, 44-46, 59-66, and 68-72 are pending. Claims 11, 13, 15-22, 25, 26, 27, 29-33, 34 (partially), 36-37, 38 (partially), 66, 68, and 69-72 are withdrawn from consideration as described above. Claims 1-4, 7-10, 12, 14, 23-24, 34, 35, 38, 44-46, and 59-65 are pending and under examination on the merits in the instant office action.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(4) because reference characters "5C and " and "5D and 5F" have both been used to designate the drawings of CD45N-CAR and sCD45/CAR on sheet 9/36. Furthermore, sheet 9/36 appears to be a duplicate of sheet 8/36, but for the label "Figures 5C and D". 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. 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. The examiner suggests deleting sheet 9.
The drawings are objected to because:
Figure.
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.
Specification
The use of the term nanobody ([0008],[0080], and p. 42 line 3), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Applicant is advised that should claim 2 be found allowable, claim 4 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7 and 65 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 7 contains the trademark/trade name Nanobody®. 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 a single domain antibody and, accordingly, the identification/description is indefinite.
Regarding claims 7 and 65 , the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 64 and 65 are 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. Claim 64 recites "wherein the undesired activation of an immune cell is activation caused by specific binding of the immune cell to normal tissue via one or more cell-surface epitopes present on normal and related abnormal mammalian tissue or mammalian tissue being targeted by an autoimmune response" However, claim 62 upon which claim 64 ultimately depends recites "wherein the mammalian tissue being targeted by an autoimmune response is selected from the group consisting of pancreatic islets; [….]; skin, thyroid, and articular joints". The functional limitations of claim 64 are broader than the functional limitations of claim 62 because claim 62 narrows the scope to a bCAR wherein the tissue being targeted by an autoimmune response is a particular tissue, but claim 64 expands the scope to specific binding of the immune cell to related abnormal mammalian tissue, rather than just mammalian tissue targeted by an autoimmune response. Claim 65 is dependent on claim 64 without resolving the 112(d) as described. 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.
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 1-4, 7-10, 12, 14, 23-24, 34, 35, 38, 44-46, and 59-65 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
At the broadest, the invention of claim 1 is directed towards a blocking chimeric antigen bCAR and a polynucleotide encoding a bCAR capable of preventing undesired activation of an immune cell comprising:
An extracellular domain that is more than about 20nm in length comprising:
A single-chain binding domain
A rigid elongation domain, and
A protease cleavage site capable of being cleaved by a protease
A transmembrane domain; and
An intracellular domain comprising a full or partial intracellular domain of a membrane phosphatase capable of dephosphorylating phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs),
wherein the protease cleavage site is linked to the intracellular domain by the transmembrane domain,
wherein the binding domain specifically binds to a cell surface epitope present on normal mammalian tissue, but absent on related abnormal mammalian or mammalian tissue being targeted by an autoimmune response (claims 1 and 44). The claims therefore encompass:
1) Any protease cleavage site capable of being cleaved by any protease under any condition. The protease cleavage site “is linked to the intracellular domain by the transmembrane domain”; however, the specification does not define “linked”. Therefore, the broadest reasonable interpretation of claims 1 and 44 is that the protease cleavage site may be linked by any distance and be in any location in the extracellular domain, so long as it is linked in a covalent or non-covalent manner to the transmembrane domain. Claims 2, 3, 23, 45, and 46 narrow the bCAR or the polynucleotide encoding the bCAR to a protease cleavage site capable of being cleaved by a disintegrin and metalloproteinase (ADAM) or a beta-secretase 1 (BACE1) and wherein the protease cleavage site comprising Lin12/Notch repeats or an ADAM protease cleavage site. Claims 4, 7, 8-10, 12, 14, 23-24, 34, 35, and 38 are ultimately dependent on claim 1 without further narrowing the scope of the protease cleavage site.
2) Regarding the binding domain specifically binding to a cell surface epitope present on normal mammalian tissue, but absent on related abnormal mammalian tissue or mammalian being targeted by an immune response, the scope encompasses any single-chain binding domain defined by the functional property of binding to a cell surface epitope present on normal mammalian tissue, but absent on related abnormal mammalian tissue or mammalian tissue being targeted by an autoimmune response. Claim 62 narrows the target to wherein the mammalian tissue being targeted by an autoimmune response is selected from the group consisting of pancreatic islets of the pancreas; digestive system; small intestine; large intestine; colon; thyroid; nervous system; skin, thyroid, and articular joints. Claim 63 narrows to wherein the mammalian tissue is human tissue. The scope of claim 62 and dependents still broadly encompasses a bCAR binding to any antigen that is not expressed on one of those tissues but is expressed on normal mammalian cells.
State of the Relevant Art
Blocking chimeric antigen receptors comprising an intracellular domain capable of dephosphorylating phosphorylated ITAMs are taught in the art. WO2015142314 to Fedorov et. al. teaches immunoresponsive cells comprising an inhibitory chimeric antigen receptor (iCAR), wherein the iCAR comprises an intracellular domain that activates intracellular signaling to decrease immune response (e.g. CTLA-4, PD-1, LAG-3, 2B4, BTLA4) (p. 8 line 27 to p. 9 line 30. Fedorov et. al. teaches that the inhibitory signaling molecules are capable of dephosphorylating TCR signaling proteins comprising ITAMs such as CD3 (See p. 6 line 29-p. 7 line 19; p. 29 lines 20-26; p. 34 lines 3-5. WO2014145252 to Milone et. al. teaches CARs designed with a component of a receptor naturally found in NK cells. The inhibitory KIR-CARs (inhKIR-CAR) comprise cytoplasmic domains bearings ITIMs, which are capable of dephosphorylating ITAMs to limit the activation of NK and T cells (p. 3 lines 14-19). Although most of these intracellular domains are capable of inducing dephosphorylation of CD3 through ITIM domains which recruit phosphatases, rather than being phosphatases themselves, blocking CARs comprising membrane phosphatase domains of PTPN6, CD45, or CD148 are known in the art (WO2015075470 to Pulé et. al.; Fig. 12; p. 5 lines 19-34; p. 13 lines 29-34).
Additionally, Pulé et. al. teaches the inhibitory CARs may have extended extracellular domains in order to promote the desired kinetic segregation between multiple activating and inhibitory CARs, thereby using Boolean logic to provide the desired activation outcome of the immune cells (p. 30 lines 6-23). Pulé et. al. teaches “When both CARs are ligated, due to differences in spacer properties, the activating and inhibiting CAR are differentially segregated allowing the activating CAR to trigger T-cell activation unhindered by the inhibiting CAR” (p. 30 line 33-p. 31 line 2; Pulé et. al. teaches compound logic gates can be made by differentially designing the spacer length of inhibitory and activating CARs (p. 33 line 5-19) and that the extracellular spacers may comprise rigid spacers such as CD2 or truncated CD22 (p. 37 lines 15-17) or immunoglobulin hinges such as IgM Fc domain (p. 37 line 11-14, see table).
CARs or bCARs comprising protease cleavage domains in the extracellular domain and linked to the transmembrane domain are also known in the art. For example, Han, X., Bryson, P.D., Zhao, Y., Cinay, G.E., Li, S., Guo, Y., Siriwon, N. and Wang, P., 2017. Masked chimeric antigen receptor for tumor-specific activation. Molecular Therapy, 25(1), pp.274-284 teaches a chimeric antigen receptor comprising a cleavable linker and a masking peptide, wherein the cleavable linker is linked to the transmembrane domain by the scFv and hinge/spacer domain (see Graphical Abstract).
Regarding CARs comprising ADAM protease cleavage domains and Lin12/Notch repeats, WO2016138034 to Lim et. al. (of record, IDS dated 7/29/2022) teaches an AND + NOT CAR wherein the inhibitory CAR comprising a SynNotch domain which comprises Lin12/Notch repeats and an ADAM protease cleavage site that releases a synthetic transcription factor into the cytoplasm and then causes transcription of an inhibitory intracellular domain (Fig. 136, [0007], [00176], [00290]). Although the synthetic Notch sites that are the target of different proteases are disclosed, all of the receptors disclosed by Lim et. al. comprise both Lin-12 Notch repeats and a binding-induced proteolytic cleavage site.
Regarding the target of the binding domain, examples of binding domains that bind to a target expressed on normal mammalian tissue but not on abnormal target tissue are known in the case of, for example, cancer. Pulé et. al. (as cited above) teach that the antigen targets the AND NOT gate is of use “when a tumour can be distinguished from normal tissue by the presence of tumour associated antigen and the loss of an antigen expressed in normal tissue”. Pulé et. al. teaches the inhibitory CAR target antigen CD34, which is expressed on normal stem cells but not AML cells (p. 32 lines 17-25, Table 6). Additionally, loss of heterozygosity of polymorphic epitopes such as HLA alleles is known in cancer. Fedorov, V.D., Themeli, M. and Sadelain, M., 2013. PD-1–and CTLA-4–based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Science translational medicine, 5(215), pp.215ra172-215ra172 teach “One strategy is to use broad classes of surface antigens that are down-regulated on tumor cells. One example is represented by human leukocyte antigen (HLA) molecules, which are found in virtually all cell types, but are down-regulated on tumors as a mechanism of tumor escape from T cell immune responses (46). Thus, allogeneic T cells expressing an iCAR against a host HLA molecule that is down-regulated on the tumor may selectively promote the GVT effect. The iCAR approach may be of particular interest in the setting of DLI as a means to protect GVHD target tissues without impairing GVT responses. Another class of antigens amiable to a similar strategy includes cell surface tumor suppressor antigens, such as OPCML, HYAL2, DCC, and SMAR1 (47–49). OPCML-v1, for example, is widely expressed in all normal adult and fetal tissues but is down-regulated in lymphomas and breast and prostate cancer. Cell surface carbohydrates, lipids, and posttranslational modifications, such as mucin-type O-glycans (core 3 O-glycans) have also been found to be down-regulated by tumors (50). Another candidate target is E-cadherin, which is highly expressed in normal skin, liver, and gut—the primary targets of GVHD (51)—but down-regulated by tumor cells undergoing an epithelial to mesenchymal transition, indicating tumor progression and metastasis (52)” (Discussion, ¶4). However, there are no examples of record of a target antigen that is expressed in normal tissue but is not expressed on tissue being targeted by an immune response such as digestive system or pancreatic islet cells. Pulé et. al. teach the use of the iCAR in autoimmune disease and using regulatory T cells rather than effector immune cells (p. 47 lines 36-41; p. 62 lines 34-35), but do not teach wherein the blocking CAR is specific for an antigen that is expressed on normal tissue but is not expressed on tissue targeted by an autoimmune response. The art does not describe what particular antigens are not expressed on the recited tissues being targeted by an autoimmune response, and it is unclear how these would be identified because, typically, what defines an autoimmune response is that it is targeting a normal tissue which would have so-called normal gene expression.
Summary of Species disclosed in the original specification
The instant specification prophetically discloses SynNotch-based bCARs [0044], [0045], which comprise a binding-dependent protease site between the elongation domain and the transmembrane domain such that binding of antigen by the binding domain causes cleavage of the extracellular domain from the transmembrane and intracellular domain and causes the cleaved intracellular phosphatase domain to no longer be excluded from the T cell synapse (Fig. 15-16) . The specification demonstrates that at least one construct of the invention is expressed by HEK293T cells. There is no evidence that the synNotch based bCARs are expressed by immune cells or can inhibit activation of the immune cells in the presence of the antigen. There are no examples using a protease cleavage domain other than synNotch, which requires both the target protease site and the Lin12/Notch repeat domains in order to be binding-dependent [00108].
The instant specification does not disclose any particular or prophetic embodiments of antigens that are expressed on normal tissue but are not expressed on mammalian tissue being targeted by an immune response. The specification particularly discloses that the synNotch CAR embodiment comprises an anti-HLA-A2 scFv (Fig. 16). There is no evidence that HLA-A2 is not expressed in mammalian tissue being targeted by an autoimmune response on record.
One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of blocking chimeric antigen receptors comprising 1) any protease cleavage site in any position linked to the transmembrane domain and 2) the required genus of bCARs that comprising a single-chain binding domain that binds to an antigen expressed on normal mammalian tissue, but not on mammalian tissue being targeted by an autoimmune response.
Summary
A genus of species is not present in the specification that shows possession of bCARs that 1) comprise any protease cleavage site capable of being cleaved by any protease wherein the protease cleavage site is comprised by the extracellular domain and linked in any manner to the transmembrane domain and 2) comprise a single-chain binding domain specific for an antigen that is present on normal mammalian tissue but is absent on mammalian tissue being targeted by an autoimmune response. Additionally, there is no clear structure/function relationship between all protease sites or all target antigens that would allow description of the genus in the absence of a representative number of species. Dependent claims are rejected for failing to sufficiently narrow the scope of the claims to overcome the written description issues as described. The examiner suggests that this rejection may be obviated by 1) narrowing the claims to a bCAR wherein the protease cleavage site comprising Lin 12/Notch repeats and an ADAM protease cleavage site and requiring the configuration wherein the protease cleavage site is disposed between the elongation domain and the transmembrane domain; and 2) deleting or amending to remove the limitations regarding an antigen that is present on normal mammalian tissue but is absent on mammalian tissue being targeted by an autoimmune response.
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, 7-10, 14, 24, 34, 35, and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2015075470 to Pulé et. al. published 28 May 2015 as evidenced by Akhouri, R.R., et. al., 2016. Architecture of human IgM in complex with P. falciparum erythrocyte membrane protein 1. Cell reports, 14(4), pp.723-736; Expasy peptide cutter of human IgM constant domain (Uniprot P01871-2); and Uniprot P01871 “IGHM_Human”.
Claim interpretation
The instant claims are broadly directed towards a polynucleotide encoding a blocking chimeric antigen receptor (bCAR) (claim 1) and a bCAR (claim 44) capable of preventing undesired activation of an immune cell comprising:
An extracellular domain that is more than about 20nm in length comprising:
A single-chain binding domain
A rigid elongation domain, and
A protease cleavage site capable of being cleaved by a protease
A transmembrane domain; and
An intracellular domain comprising a full or partial intracellular domain of a membrane phosphatase capable of dephosphorylating phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs),
wherein the protease cleavage site is linked to the intracellular domain by the transmembrane domain,
wherein the binding domain specifically binds to a cell surface epitope present on normal mammalian tissue, but absent on related abnormal mammalian tissue being targeted by an autoimmune response.
Regarding the extracellular domain that is “more than about 20nm in length”, the instant specification does not define “about”. The specification states “Elongated CD48 (CD48-CD22, right inhibits T cell antigen recognition by formation contacts in which the intermembrane distance (>20 nm) is too great for the TCR to engage the pMHC” [0033]. Therefore, in “more than about 20 nm in length”, the length of an extracellular domain that is too long for a TCR (or CAR) to engage target antigen will be interpreted as “more than about 20 nm in length”.
Regarding the “rigid elongation domain”, this is not defined in the specification or the art. The specification suggests that some examples of rigid elongation domains are fibronectin type III repeats or Ig domains that include the motifs of the Ig fold. All proteins that comprise a fibronectin type III repeat or Ig domains that include the motifs of the Ig fold will be interpreted as sufficiently rigid [0082].
Regarding the “full or partial intracellular domain of a membrane phosphatase capable of dephosphorylating phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs)”, the examiner interprets that it is the “full or partial intracellular domain” that must be capable of dephosphorylating ITAMs, rather than any partial intracellular domain of a membrane phosphatase, wherein the membrane phosphatase is capable of dephosphorylating ITAMs.
Pulé et. al. teaches first and second chimeric antigen receptors and polynucleotides encoding the first and second chimeric antigen receptors (CARs), wherein the second CAR is an inhibitory CAR comprising a ligation-off inhibitory endodomain (reads on blocking chimeric antigen receptor) (Abstract). The inhibitory CAR comprises an extracellular binding domain, a transmembrane domain, and an inhibitory endodomain (reads on intracellular domain). The inhibitory endodomains comprise the intracellular signaling regions of PTPN6, CD148, or CD45, which are phosphatases capable of dephosphorylating phosphorylated ITAMs (p. 42 lines 22-26, p. 43 lines 21-37). In particular, Pulé et. al. teaches an inhibitory CARs with AND NOT gates and extended spacers comprising the human-IgM-Hinge-CH2CH3-CH4 spacer (p. 36, see the table at the bottom; reads on “rigid elongation domain”). As evidenced by Akhouri, R.R., et. al., the IgM “core” comprised of two IgM Hinge-CH2CH3-CD4 is approximately 16 nm (Fig. 2A and C, p. 724 right column), and therefore inhibitory CAR extracellular domain comprising the IgM spacer plus binding domain would be longer than about 20 nm.
Regarding protease cleavage sites, the IgM spacer comprises many protease cleavage sites capable of being cleaved by a protease as evidenced by Expasy peptide cutter of human IgM constant domain (Uniprot P01871-2), the IgM constant domain spacer comprises protease target sites capable of being cut by the proteases: Arg-C proteinase, Asp-N endopeptidase, , Caspase 1, Chymotrypsin, Clostripain, Glutamyl endopeptidase, Endoproteinase LysC, and LysN, Pepsin, Proline endopeptidase, proteinase K, staphylococcal peptidase I, thermolysin, and trypsin.
Pulé et. al. teaches that the endodomain is capable of inhibiting T cell signaling by dephosphorylation of ITAMs (p. 42 lines 22-26).
Regarding extracellular binding domains, Pulé et. al. teaches that the antigen binding domains are single-chain antigen binding domains (p. 34 lines 20-26). The antigen targets the AND NOT gate is of use “when a tumour can be distinguished from normal tissue by the presence of tumour associated antigen and the loss of an antigen expressed in normal tissue”. Pulé et. al. teaches the inhibitory CAR target antigen CD34, which is expressed on normal stem cells but not AML cells (p. 32 lines 17-25, Table 6).
Pulé et. al. teaches encoding nucleic acids of the second CAR (i.e. the inhibitory CAR) (p. 46 lines 32-33; p. 49 lines 37-38).
Regarding claim 7, Pulé teaches the single domain binding domains are scFvs (p. 2 lines 20-21, Fig 12-13, p. 5 lines 19-41). The binding domain may comprise an scFv derived from a monoclonal antibody, a natural ligand of the target antigen, a peptide with sufficient affinity for the target; a single domain antibody; an artificial single binder such as a Darpin (designed ankyrin repeat protein; or a single-chain derived from a T-cell receptor (p. 34 lines 20-26).
Regarding claim 8 and 24, the endodomains comprise the intracellular signaling regions of or CD148 or CD45 (p. 43 lines 21-37). The inhibitory CARs comprise scFvs as described for claim 7 above.
Regarding claims 9 and 10, as evidenced by Uniprot P01871 “IGHM_Human”, the IgM constant region is an immunoglobulin comprising Ig fold domains.
Regarding claim 14, Pulé teaches that the abnormal tissue is a tumor (p. 32 lines 17-25, Table 6; reads on malignant tumor).
Regarding claim 34, Pulé teaches the nucleic acid comprised by a vector linked to an internal ribosome entry sequence or a second promoter (reads on control element; p. 14 lines 29-32).
Regarding claim 35, Pulé et. al. teaches immune cells comprising the polynucleotide according to claim 1.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kathleen CunningChen whose telephone number is (703)756-1359. The examiner can normally be reached Monday - Friday 11-8:30 ET.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GARY B NICKOL/Supervisory Patent Examiner, Art Unit 1645