DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application claims priority to US provisional application 63/230574, filed on 06 August 2021, and is a 371 of PCT/US22/74615, filed on 05 August 2022. The effective filing date is 06 August 2021.
Information Disclosure Statement
The information disclosure statement (IDS), filed on 03 April 2024 was considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-15 are the original claims, filed on 25 January 2024. In the in the preliminary amendments, of 25 January 2024, claims 4, and 11-14 were amended. Claims 1-15 are pending and the subject of this office action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
WRITTEN DESCRIPTION
(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 6-10 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 claims contain 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.
The claims are drawn to modified immune cells, comprising an anti-EGFR antigen binding domain. Claim 6 refers to anti-EGFR antigen binding domains, comprising variable regions that share at least 80 % sequence identity to SEQ ID Nos: 7, 26, 29, or 30 (heavy chain) or SEQ ID Nos: 10, 27, 31, or 32 (light chain). Claims 7 and 10 refer to either a scFv or CAR amino acid sequences, respectively, comprising the aforementioned antigen binding domains. The claims encompass a genus of heavy and light chain variable regions comprising up to 20% variability (≤ 80% identity) in the both the heavy and light chain variable regions, which are claimed to specifically bind EGFR in the context of a CAR. Claims 8 and 9 refer to the polynucleotide sequences encoding the antigen binding domain and CAR, respectively.
The instant disclosure, however, does not provide an adequate number of species of the claimed genus nor does the disclosure provide a structure-function correlation that would allow for an ordinarily skilled artisan to envision what variation can occur in the heavy and light chains, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
The current disclosure discusses modified immune cells, comprising chimeric antigen receptors, that comprise anti-EGFR antigen binding domains, comprising CDRs defined by SEQ ID Nos: 1-3 (heavy chain) and SEQ ID Nos: 4-6 (light chain). These antigen binding domains, with 100% sequence identity in the CDR regions of the heavy and light chain variable regions (encompassed in SEQ ID Nos: 7, 26, 29, 30, 10, 27, 31, 32, 14, 16, 28, 18, 20, and 22), represents the binding domains/scFvs/CARs that applicant was in possession of at the time of filing. It is noted that there would be support for 100% identity of the full complement of the six CDRs together with some percentages of identity in the framework region or regions of the CAR not affecting antigen binding that would have been predictable.
The state of the art around the effective filing date of the claimed invention also does not provide an adequate number of species of the claimed genus or the necessary structure-function correlation. Rather, the art demonstrates that antibody functionality was known to depend on the entire antibody structure, particularly a full complement of six CDRs. Chiu ML, et al. (2019) Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel). Dec 3;8(4):55 teaches that the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). Here, Chiu teaches that the interaction between the heavy and light chain variable domains effects the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably determine which amino acids in which CDR regions could be modified such that the antigen binding domain would still perform the function of binding EGFR.
Rabia L, et al. (2018) Understanding and overcoming tradeoffs between antibody affinity, specificity, stability, and solubility. Biochem Eng. J. 15(137); 365-374 discusses the challenges with optimizing antibody properties and states “the most important antibody properties relate to their natural functions, such as their high binding affinity and specificity mediated by their complementarity-determining regions (CDRs) within the variable regions... Other key natural antibody properties include their effector functions — such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC)- which are mediated by their constant regions” (page 2, paragraph 1). Rabia further teaches that “most antibodies identified during the initial discovery process are not suitable for therapeutic use and require additional optimization. For example, the binding affinities of some lead antibodies are not high enough for therapeutic applications” (page 2, paragraph 3). Rabia goes on to state that “natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity...antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations” (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that “a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that co-optimize multiple antibody properties” and that “future efforts will also need to improve structural predictions of antibody CDRs — especially the long and highly variable heavy chain CDR3-to accurately predict CDR mutations that are beneficial to different antibody properties” (page 9, paragraph 4 — page 10 paragraph 2).
Based on the teachings of Rabia, introducing mutations in antibody structure, particularly in the CDR regions, is not predictable and requires experimentation following mutation to ensure that binding affinity is maintained and a stable antibody is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and demonstrated how these methods are not robust enough yet to yield predictable results. This teaching demonstrates that modifications to the sequences of the claimed invention could result in an antigen binding domains that are not suitable for its intended role in the context of a CAR.
Overall, it is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species of the claimed genus at the time of filing. Specifically, it is not evident that applicant was in possession of a representative number of antigen binding domains with variation in the CDRs, which are the known binding regions of the antibody/antigen binding domain, that performed the claimed function. Additionally, there is no disclosed or art recognized relationship between antibody structure/antigen binding region and function which would allow for the predictable modification of the claimed antigen binding domain with up to 20% variance anywhere in the structure, particularly in the CDRs, while maintaining the claimed functions. Therefore, the instant claims are found to not meet the written description requirement.
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.
(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.
Claims 1-3, and 12-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2020142727 A1 (herein Alkhateeb). Alkhateeb teaches compositions and methods for treating cancer, comprising immune cells (e.g. an engineered T cell), with enhanced sialidase/neuraminidase activity (Abstract). The method teaches a method for treating cancer, comprising the administration of an isolated immune cell, that may be engineered/modified to express a CAR (Relevant to instant claims 14 and 15) ([0022] and [0030]). It is also taught that there is a growing body of evidence establishing a role of glycans, sialoglycans in particular, with various pathophysiological steps of tumor progression ([0004]). Cancer cells often display altered degrees of cell surface sialylation, relative to non-cancerous cells, which results in the existence of sialylated tumor-associated carbohydrate antigens. In an attempt to address this growing body of evidence, in the form of an immunotherapy, Alkhateeb teaches an anti-cancer treatment, comprising CAR T cell therapy, in which sialidase activity is enhanced (i.e. sialidase is introduced into, up regulated, or otherwise increased in the immune cell) ([0007]). To this end, it is taught that the CAR T cell may comprise an exogenous nucleotide sequence encoding a sialidase, either of eukaryotic or prokaryotic origin ([0008-00010]). It is further taught that the exogenous sialidase may include an N-terminal signal sequence, in order to enable secretion ([00146]). In regard to the CAR element, it is taught that the antigen binding domain targets a cancer/tumor-associated antigen, and EGFR is among the suggested antigens (Relevant to instant claim 3) ([0013]). An exemplary CAR is also described, comprising an scFv antigen binding domain (m912-specific) fused to CD8/4-1BB/CD3 domains (Relevant to instant claim 2) ([00252]). The format of the antibody is taught to include Fab, Fab’, (Fab’)2, Fv, single chain antibodies (e.g, scFv), minibodies, and diabodies, depending on the embodiment ([0090]). In regard to the nature of the engineered immune cell, it is taught that the cell may be a T cell, including “CD4+/CD8+ double positive T-cells, CD4+ helper T-cells, e.g., Th1 and Th2 cells, CD4+ T-cells, CD8+ T-cells (e.g., cytotoxic T-cells), tumor infiltrating lymphocytes (TILs), memory T-cells (e.g, central memory T-cells and effector memory T cells), naive T-cells, and the like” (Relevant to instant claim 12)( [0049]). Additionally, it is taught that T cell may autologously derived (Relevant to instant claim 13). Alkhateeb, teaches that expression of a neuraminidase/sialidase in a cell culture system, comprising CAR T cells and Raji cells, leads to increased expression of IFN-γ (Figure 8A), IL-2 (Figure 8B) and TNF-α (Figure 8C) ([00249]).
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 4 is rejected under 35 U.S.C. 103 as being unpatentable over WO2020142727 A1 (herein Alkhateeb), in view of Sethi MK, et al. (2015) In-depth N-glycome profiling of paired colorectal cancer and non-tumorigenic tissues reveals cancer-, stage- and EGFR-specific protein N-glycosylation. Glycobiology. 2015 Oct;25(10):1064-78 (herein Sethi), Häuselmann I, Borsig L. (2014) Altered tumor-cell glycosylation promotes metastasis. Front Oncol. 2014 Feb 13;4:28 (herein Hauselmann), and Britain CM, et al. (2018) Sialylation of EGFR by the ST6Gal-I sialyltransferase promotes EGFR activation and resistance to gefitinib-mediated cell death. J Ovarian Res. 2018 Feb 5;11(1):12 (herein Britain).
Alkhateeb teaches a modified immune cell, comprising a nucleic acid encoding a CAR, and a second nucleic acid encoding a neuraminidase, as discussed for the 35 U.S.C. 102(a)(1) rejections of claims 1-3 and 12-15. Alkhateeb, does suggest that the antigen binding domain of the CAR may target EGFR, but does not explicitly teach EGFR over the many other example embodiments. Sethi, Hauselmann, and Britain teach this deficiency.
Hauselmann provides a review of the state of the art, in regard to the understanding of cancer-associated aberrant glycosylation and its role in metastasis (Abstract). Hauselmann teaches that malignant transformation of cell is associated with aberrant glycosylation, such as an increased presence of sialic acid and abnormal branching of N-linked glycans, on the cell surface. Hauselmann teaches that in nearly every cancer type, upregulation of glycosyltransferases has been detected (Section: General Mechanism for Altered Glycosylation in Cancer, paragraph 4). In particular, a general increase in sialylation is associated with a metastatic cell phenotype. It is also taught that overexpression of neuraminidase 1 in colon cancer cells led to reduced liver metastasis in mice, and silencing of neuraminidase 1 led to increase cell migration, invasion, and adhesion in vitro. The authors also teach that sialic acid-binding lectins (siglecs) play various roles in immune-regulation (mainly immune inhibitory) (Section: Siglecs). These teachings show that aberrant sialyation of cell surface proteins has a general disrupting effect on the tumor microenvironment in various cancers, via effects on cell-surface protein themselves and the altered activity of siglecs.
Sethi et al teach that dysregulation of sialylation directly alters EGFR. Sethi relates to a study aimed at uncovering the structure-function relationships of protein glycosylation and identifying glycoprotein marker for colorectal cancer research (Abstract). In this study, the authors performed label-free quantitative glycomics using mass spectrometry-based analysis to profile the N-linked glycosylation changes of EGFR, associated with colorectal cancer malignancies (Abstract). Sethi teaches that sialylation of EGFR was significantly up-regulated in colorectal cancer tissue, compared to healthy tissue (Results: Quantitative N-glycoprofiling reveals significant CRC-specific N-glycosylation). Thus establishing a link between aberrant sialylation and EGFR.
Britain teaches that increased levels of sialylation, resulting from upregulation of the ST6Gal-1 sialyltransferase, leads to increased cell signaling and promotes tumor survival (Background). It is taught that aberrant sialyation of EGFR results in increased receptor activity (Discussion, paragraph 2). This causes both increased basal tyrosine kinase activity as well as EGF-induced activity, both of which are well-known to contribute to malignant transformation. This study indicates that sialylation of EGFR has an extremely potent effect on immune dysregulation.
In light of the teachings of Sethi, Hauselmann, and Britain, it would have been obvious to use an antigen binding domain targeted towards EGFR in the method of treating cancer, taught by Alkhateeb, comprising a CAR and secreted neuraminidase. Hauselmann, establishes a general effect of upregulation of sialyltransferases, Sethi teaches that EGFR is confirmed to be a target of dysregulated sialyltransferase in cancer cells, and Britain establishes how catastrophic excessive sialylation of EGFR is in the context of transformation towards malignancy. These teachings provide clear motivation for the targeting of tumor cells, containing cell-surface EGFR, with CAR T cells modified to secrete a sialidase/neuraminidase.
Claims 5-10 are rejected under 35 U.S.C. 103 as being unpatentable over WO2020142727 A1 (herein Alkhateeb), Sethi MK, et al. (2015) In-depth N-glycome profiling of paired colorectal cancer and non-tumorigenic tissues reveals cancer-, stage- and EGFR-specific protein N-glycosylation. Glycobiology. 2015 Oct;25(10):1064-78 (herein Sethi), Häuselmann I, Borsig L. (2014) Altered tumor-cell glycosylation promotes metastasis. Front Oncol. 2014 Feb 13;4:28 (herein Hauselmann), and Britain CM, et al. (2018) Sialylation of EGFR by the ST6Gal-I sialyltransferase promotes EGFR activation and resistance to gefitinib-mediated cell death. J Ovarian Res. 2018 Feb 5;11(1):12 (herein Britain), in view of US20140322212 A1 (herein Brogdon) and WO2007062037 A2 (herein McKenna).
In regard to claim 9, Alkhateeb, Sethi, Hauselmann, and Britain teach a modified immune cell, that comprises nucleic acids that encode a secreted neuraminidase and a chimeric antigen receptor, comprising a transmembrane domain, an intracellular domain, and an EGFR-targeted antigen binding domain, as discussed in the 35 U.S.C. 103 rejection of claim 4. Alkhateeb, Sethi, Hauselmann, and Britain do not teach a modified immune cell, wherein the modified immune cell comprises a polynucleotide encoding a CAR, comprising an amino acid that is between 80-100 % identical to the sequences defined in SEQ ID Nos: 18, 20, or 22. Brogdon and McKenna teach these deficiencies.
McKenna relates to hybrid antigen binding moieties, in which one polypeptide chain comprises an antigen binding domain, as well as methods for preparing, and using these moieties for diagnosis and/or therapy (Abstract). In an exemplary embodiment of the inventive concept, the authors disclose a fusion polypeptide, comprising a scFv targeting EGFR (SEQ ID NO: 79), that shares 100% sequence identity with SEQ ID NO: 16 referenced in claim 7. This sequence comprises the heavy (SEQ ID NO:7) and light (SEQ ID NO: 10) chain variable regions defined in claim 6, as well as the CDRs defined in claim 5 (SEQ ID Nos: 1-6), as shown below, with variable light chain and heavy chains colored in green and blue, respectively.
LCDR1
Ref GGGGSGGGGSGGGGSLEADILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGK 420
Instant ------------------DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGK 42
******************************************
LCDR2 LCDR3
Ref SFKGLIYHGTNLDDEVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPWTFGGGT 480
Instant SFKGLIYHGTNLDDEVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPWTFGGGT 102
************************************************************
HCDR1
Ref KLEIKRGGGGSGGGGSGGGGSDVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIR 540
Instant KLEIKRGGGGSGGGGSGGGGSDVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIR 162
************************************************************
HCDR2
Ref QFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLNSVTIEDTATYYCVTA 600
Instant QFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLNSVTIEDTATYYCVTA 222
************************************************************
HCDR3
Ref GRGFPYWGQGTLVTVSA 617
Instant GRGFPYWGQGTLVTVSA 239
*****************
Brogdon relates to chimeric antigen receptors, targeted to CD123, and their use for treating leukemia (Abstract). Brogdon teaches chimeric antigen receptors, comprising a leader sequence, CD8a hinge, CD8 transmembrane region, 4-1BB intracellular co-stimulatory domain, and a CD3[Symbol font/0x7A] activation domain (Figure 7b and [0389]). The disclosed sequences share 100% sequence identity with SEQ ID NO: 22 of instant claim 10, with the exception of the antigen binding region corresponding to the scFv, shown below using SEQ ID NO: 119. Brogdon teaches that scFv sequences can be added to the CAR constructs, in a modular fashion, as demonstrated by the multiple clones, differing only in scFv sequence (Figures 7a and 7b, and [0389]).
Antigen binding region
Ref SEQ ID NO:119 MALPVTALLLPLALLLHAARPGSQVQLQQP-GAELVRPGASVKLSCKASGYTFTSYWMNW 59
Instant SEQ ID NO: 20 MALPVTALLLPLALLLHAARPGSDILMTQSPSSMSVSLGDTVSITCHSSQDI--NSNIGW 58
***********************:: : * .: * * :*.::*::* . :.*
Antigen binding region
Ref SEQ ID NO:119 VKQRPDQGLEWIGRIDPYDSETHYNQKFKDKAILTVDKSSSTAYMQLSSLTSEDSAVYYC 119
Instant SEQ ID NO: 20 LQQRPGKSFKGLIYHGT-NLDDEVPSRF------SGSGSGADYSLTISSLESEDFADYYC 111
::***.:.:: : . : : . .:* : . *.: : :*** *** * ***
Antigen binding region
Ref SEQ ID NO:119 ARG-NWDDYWGQGTTLTVSSGGGGSGGGGSSGGGSDVQITQSPSYLAASPGETITINCRA 178
Instant SEQ ID NO: 20 VQYAQFPWTFGGGTKLEIKRGGGGSGGGGSGGGGSDVQLQESGPSLV-KPSQSLSLTCTV 170
.: :: :* **.* :. **********.*******: :* *. .*.:::::.* .
Antigen binding region
Ref SEQ ID NO:119 S-KSISKDLAW--YQEKPGKTNKLLI---YSGSTL-QSGIPSR--FSGSGSGTDFTLTIS 229
Instant SEQ ID NO: 20 TGYSITSDFAWNWIRQFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLN 230
: **:.*:** :: **:. : : ***.* : .: ** :: . * .:* * :.
Antigen binding region
Ref SEQ ID NO:119 SLEPEDFAMYYCQQHNKYPYTFGGGTKLEIKASSGTTTPAPRPPTPAPTIASQPLSLRPE 289
Instant SEQ ID NO: 20 SVTIEDTATYYCVTAGRGFPYWGQGT-LVTVSASGTTTPAPRPPTPAPTIASQPLSLRPE 289
*: ** * *** .: :* ** * ::***************************
Ref SEQ ID NO:119 ACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFM 349
Instant SEQ ID NO: 20 ACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFM 349
************************************************************
Ref SEQ ID NO:119 RPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDV 409
Instant SEQ ID NO: 20 RPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDV 409
************************************************************
Ref SEQ ID NO:119 LDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLS 469
Instant SEQ ID NO: 20 LDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLS 469
************************************************************
Ref SEQ ID NO:119 TATKDTYDALHMQALPPR 487
Instant SEQ ID NO: 20 TATKDTYDALHMQALPPR 487
******************
It would have been obvious to combine the teachings Brogdon and McKenna with the modified immune cells taught by Alkhateeb, Sethi, Hauselmann, and Britain. McKenna teaches a scFv, specific to EGFR, and has demonstrated that this scFv is capable of binding EGFR with an appreciable affinity, as demonstrated by the hybrid molecules, comprising the scFv, successfully binding their intended target in vivo ([0422]). Brogdon teaches a chimeric antigen receptor sequence, comprising a leader sequence, CD8a hinge, CD8 transmembrane region, 4-1BB intracellular co-stimulatory domain, and a CD3[Symbol font/0x7A] activation domain, to which scFv sequences may be swapped in (Figure 7b and [0389]). Brogdon also demonstrates that T cells transduced with the CAR element display anti-tumor activity in vitro, using multiple scFv sequences ([0426-0427]). It would have been obvious to one skilled in the art, at the time of filing, to swap the provenly effective scFv, taught by McKenna, into the provenly effective CAR sequence taught by Brogdon, for the purpose of embodying the anti-EGFR CAR cell taught by Alkhateeb, Sethi, Hauselmann, and Britain. McKenna and Brogdon both teach elements that are shown to be effective, and by swapping in the scFv, taught by McKenna, into the CAR, taught by Brogdon, as the applicant has done, one arrives at a product that possesses entirely predictable properties.
In regard to claims 8 and 9, the amino acid sequence of an anti-EGFR CAR, that embodies the limitation of claim 4 are taught by Alkhateeb, Sethi, Hauselmann, Britain, Brogdon, and McKenna, as discussed for the 35 U.S.C. 103 rejections of claims 5-10. Designing a polynucleotide sequence encoding a protein of a specific amino acid sequence, as well optimizing codon for its intended expression system is routine in the field and would have been obvious to one skilled in the art, at the time of filing.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over WO2020142727 A1 (herein Alkhateeb), in view of King T, et al. (2019) Co-expression of an engineered cell-surface sialidase by CART cells improves anti-cancer activity of NK cells in solid tumors. Cytotherapy. Volume 21, Issue 5, Supplement, 2019, Page S27 (herein King).
Alkhateeb teaches a modified immune cell, comprising a nucleic acid encoding a CAR, and a second nucleic acid encoding a neuraminidase, as discussed for the 35 U.S.C. 102(a)(1) rejections of claims 1-3 and 12-15. Alkhateeb, does suggest that the neuraminidase may be of prokaryotic origin ([0008-00010]), but does not explicitly teach the use of a polynucleotide encoding a Clostridium perfingens neuraminidase. King teaches this deficiency.
King teaches a therapeutic method comprising anti-Tn-MUC1 CAR T cells, which express a novel human sialidase (Methods, Results, and Conclusion). In this study, the authors note that when prostate cancer cell lines are treated with a Clostridium perfingens neuraminidase, anti-Tn-MUC1 CAR T cells, and NK cells show enhanced IFN-γ production and improved cytotoxic effects (Methods, Results, and Conclusion).
It would have been obvious to combine the teachings of King (combining a Clostridium perfingens neuraminidase with a CAR T cell therapy) with those of Alkhateeb (a modified immune cell, comprising a nucleic acid encoding a CAR, and a second nucleic acid encoding a neuraminidase). One would have been motivated to use Clostridium perfingens neuraminidase in the system taught by Alkhateeb, due to its proven effect in a CAR T cell system, as taught by King. This combination presents a high likelihood of success, as the secretion of the neuraminidase would be functionally equivalent to the external application, described by King.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
Prosecution Insights