26Notice 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 .
Claims 1-6, 13, 15, 17-18, 21-23, 29, 37, 41-42, 57-58 and 66 are pending.
Applicant’s election of Group I that read on (A) SEQ ID NO: 28 as the species of chimeric receptor, (B) SEQ ID NO: 1 (anti-Aβ scFv) as the species of single-chain variable antibody fragment (scFv), (C) FCERG as the species of first intracellular phagocytic signaling domain, (D) MRC1 as the species of second intracellular phagocytic signaling domain and (E) CD8 as the species of transmembrane domain in the reply filed on April 24, 2026 is acknowledged. 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Claims 2, 22-23, 29, 37, 42 and 66 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1, 3-6, 13, 15, 17-18, 21, 41, 57 and 58, drawn to a particular chimeric receptor and method of treating a subject diagnosed with or at risk of developing a neurodegenerative disease that read on (A) SEQ ID NO: 28 as the species of chimeric receptor, (B) SEQ ID NO: 1 (anti-Aβ scFv) as the species of single-chain variable antibody fragment (scFv), (C) FCERG as the species of first intracellular phagocytic signaling domain, (D) MRC1 as the species of second intracellular phagocytic signaling domain and (E) CD8 as the species of transmembrane domain, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/163,016, filed March 18, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on April 24, 2026 and April 2, 2024 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
The listing of references in the specification at pages 73-76 is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings filed on September 5, 203 are acceptable.
Specification
The preliminary amendment to the specification filed September 15, 2023 has been entered.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1-3, are objected to because the claims recite non-elected embodiments.
Claim 13 is objected to because of the following informalities: the claim uses the abbreviation MRC1, FCεRIγ, FCERG without first defining it. To clarify the claim, applicant should first spell out the full term before using an abbreviation. Given the subject matter of the specification, the examiner presumes that "MRC1" stands for "mannose receptor C-type 1 (MRC1)" and “FCεRIγ (FCERG)” stands for “high-affinity immunoglobulin epsilon receptor subunit gamma (FCεRIγ or FCERG). 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 13 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 13 recites the limitation "the first intracellular phagocytic signaling domain" in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claims 1, 3-4, 17 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: the chimeric receptors in claims 1, 3, 4, 17 comprise different extracellular binding domains, e.g., single-chain variable antibody fragments (scFvs) that have binding affinity to different molecule, e.g., amyloid beta peptide, tau protein or α-synuclein protein and the (scFvs) do not share a substantial feature, e.g., heavy and light chain variable domains and a common use, e.g., same binding specificity that flows from the substantial structural feature. In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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, 3-6, 13, 15, 17-18, 21, 41, 57 and 58 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 1 encompasses any chimeric receptor comprising:(i) an intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide, tau protein or a-synuclein protein, and (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the scFv comprises an amino acid sequence having at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% sequence identity to any of SEQ ID NOs: 1 (elected species).
Claim 3 encompasses any chimeric receptor comprising:(i) a first intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide, tau protein or a-synuclein protein, (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, and (iv) a second intracellular phagocytic signaling domain fused to the first intracellular phagocytic signaling domain.
Claim 4 encompasses the chimeric receptor of claim 2, wherein the scFv comprises an amino acid sequence having at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% sequence identity to any of SEQ ID NOs: 1-6.
Claim 5 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain comprises a hinge domain.
Claim 4 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain is covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain by one or more linkers.
Claim 13 encompasses the chimeric receptor of claim 1, wherein the first intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a MRC1 signaling domain, a MEGF10 signaling domain, a DAP12 signaling domain, a MERTK signaling domain, a FCERIy (or FCERG) signaling domain (elected species), a M6PR signaling domain, or a CLEC4L signaling domain.
Claim 15 encompasses the chimeric receptor of claim 3, wherein the first intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a MRC1 signaling domain, a MEGF10 signaling domain, a DAP12 signaling domain, a MERTK signaling domain, a FCERG signaling domain (elected species), a M6PR signaling domain, or a CLEC4L signaling domain; and the second intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a MRC1 signaling domain (elected species), a MEGF10 signaling domain, a DAP12 signaling domain, a MERTK signaling domain, a FCERG signaling domain, a M6PR signaling domain, or a CLEC4L signaling domain.
Claim 17 encompasses the chimeric receptor of claim 1, wherein the chimeric receptor comprises an amino acid sequence having at least 85%, at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% sequence identity to any of SEQ ID NOs: 26-43 (SEQ ID NO: 28 as the elected species).
Claim 18 encompasses the chimeric receptor of claim 1, wherein the chimeric receptor comprises a second extracellular binding domain.
Claim 21 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain is a TREM2 transmembrane domain, a MRC1 transmembrane domain, a MEGF10 transmembrane domain, a DAP12 transmembrane domain, a MERTK transmembrane domain, a CD8 transmembrane domain (elected specie), a M6PR transmembrane domain, or a CLEC4L transmembrane domain.
Claim 41 encompasses the chimeric receptor of claim 1, wherein the modified cell is an astrocyte.
Claim 57 encompasses a method of treating a subject is diagnosed with or at risk of developing a neurodegenerative disease, disorder, or condition, the method comprising: administering to the subject the modified cell of claim 41.
Claim 58 encompasses a method of preventing a neurodegenerative disease, disorder, or condition, the method comprising: administering to a subject the modified cell of any one of claim 41.
Regarding antibody, the specification defines as follow:
[0040] An “antibody” refers to an immunoglobulin molecule capable of specific or selective binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” encompasses not only intact (e.g., full-length) polyclonal or monoclonal antibodies, but also antigen-binding fragments thereof (such as Fab, Fab′, F(ab′)2, Fv), single chain (scFv), mutants thereof, fusion proteins comprising an antibody portion, humanized antibodies, chimeric antibodies, diabodies, linear antibodies, single chain antibodies, multispecific antibodies (e.g., bispecific antibodies) and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity or selectivity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. An antibody includes an antibody of any class, such as IgD, IgE, IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant domain of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
Regarding scFv antibody encompassed by the claimed chimeric receptor that binds to any amyloid beta peptide, the specification discloses just three scFv antibodies. Anti-Aβ9 scFv comprises the amino acid sequence of SEQ ID NO: 1, anti-Aβ2.1.3 scFv comprises the amino acid sequence of SEQ ID NO: 2, anti-Aβ scFv comprises the amino acid sequence of SEQ ID NO: 3.
However, the specification does not describe the structure of any and all possible scFv antibodies that bind to any amyloid beta peptide encompassed by the claimed chimeric receptor (claims 1, 3). The specification does not describe the structure, e.g., amino acid sequences of heavy chain variable domain and light chain variable domain of a sufficient number of species of the genus of scFvs encompassed by the claimed chimeric receptors. The specification does not describe the structure-identifying information about the claimed chimeric receptor, nor describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed chimeric receptor themselves.
Even assuming the scFv comprises any one of SEQ ID NO: 1-3, the specification does teach where and what amino acids within the full-length sequence of any one of SEQ ID NO: 1-3 to be substituted, deleted, added or a combination thereof such that the modified variant having at least 85%m 90% or 95% identity to any one of SEQ ID NO: 1-3 still maintains antigen binding.
Regarding any intracellular phagocytic signaling domain, the specification discloses human FCERG comprises the amino acid sequence of SEQ ID NO: 11, human MRC1 comprises the amino acid sequence of SEQ ID NO: 12, mouse FCERG comprises the amino acid sequence of SEQ ID NO: 18, mouse MRC1 comprises the amino acid sequence of SEQ ID NO: 19, dual human FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 15, dual human MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 16, mouse dual FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 24 and mouse MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 25.
Regarding chimeric phagocytic receptor (CPR), the specification discloses chimeric receptors that bind to amyloid beta and comprise the amino acid sequence of SEQ ID NO: 26-35, 42-43, see para. [0100].
However, the specification does not teach where and what amino acid within the full-length sequence of any one of SEQ ID NO: 26-35, 42 and 43 to be substituted, deleted, added or a combination thereof such that the modified chimeric receptor having at least 85%m 90% or 95% identity to any one of SEQ ID NO: 26-35, 42 and 43 maintains binding and effector functions (claim 17).
At the time the application was filed, it is well established in the art that even a single CDR substitution can disrupt antigen binding as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA Vol 79 page 1979, 1982; PTO 892). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
Ito et al (FEBS Letters 309(1): 85-88, 1992; PTO 892) teaches substitution of histidine at various positions in an anti-lysozyme antibody. The L3A mutant contained a histidine in place of tyrosine in CDR3 of the light chain and the resulting mutant antibody lost its ability to bind to lysozyme antigen in an ELISA assay, see section spanning left and right column of page 86.
Piche-Nicholas et al MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Regarding treatment, the specification discloses:
[0035] The terms “ameliorate” and “treat” are used interchangeably and include both therapeutic and prophylactic treatment. Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a neurodegenerative disease or disorder described herein).
Regarding “disease”, the specification discloses:
[0045] “Disease” means any condition or disorder that damages or interferes with the normal function of a cell, tissue, organ or organism. Exemplary diseases of the disclosure are neurodegenerative diseases.
Regarding “subject”, the specification discloses:
[0049] The term “subject” includes organisms which are capable of suffering from a disorder as described herein or who could otherwise benefit from the administration of a compound of the present disclosure, such as human and non-human animals. Preferred humans include human patients suffering from or prone to suffering from diseases or disorders as discussed above, as described herein. Mammalian species that may benefit from the disclosed methods of treatment include, but are not limited to, apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters. A “subject in need of treatment” includes a subject diagnosed, e.g., by a medical or veterinary professional, as suffering from or susceptible to a neurodegenerative disease, disorder or condition described herein.
The specification exemplifies:
[0205] In vivo CPR prevention and clearance assessment. To evaluate the ability of CPR to prevent amyloid pathology, astrocytes are selectively transduced using rAAV-PHP.eB-GFAP-CPR and evaluate effects on amyloid pathology in CRND8 mice, a transgenic model that overexpresses mutant human amyloid protein precursor (APP) at levels approximately 5-fold higher than endogenous murine APP (see Chakrabarty, et al. Neuron 85, 519-533 (2015), incorporated herein by reference). For the prevention paradigm newborn CRND8 are injected with rAAV-PHP.eB-GFAP-CPR (with FCER1G, MRC1, MERTK, and CLEC4L with a non-specific CPR, anti-pan Aβ scFv alone, and GFP used as controls) (ICV, 4×10.sup.10 viral genomes/pup) and assess Aβ levels and plaque burden at 3 months. Each construct is delivered to 4-5 litters, resulting in −20 transgenic mice, of whom half will reach 3 months of age. Based on extensive experience with this strain, this cohort size allows to detect significant changes of 25% in amyloid levels. Small sub-cohorts on non-transgenic littermates at 4 weeks old are harvested to evaluate transduction and tropism.
[0206] At 3 months, the age at which substantial plaque formation is typically observed in these mice, one hemibrain is fixed and stained for amyloid immunoreactivity burden with anti-pan-Aβ antibody, Aβ5-biotin, and Thio-S. The other hemibrain is fractionated and Aβ levels are quantified by ELISA from RIPA-soluble fraction, SDS-soluble, and SDS-insoluble, formic acid-soluble fractions. Astrogliosis and microgliosis are evaluated using glial fibrillary acid protein (GFAP) and ionized calcium-binding molecule-1 (IBA-1) antibodies, respectively. Image analysis is done following scanning whole slides with the Aperio System and analysis of immunoreactivity burden by ImageScope program (Aperio, CA). Neuron counts in specific areas of the hippocampus and cortex where neurodegenerative may be observed by gross H&E analysis are also assessed quantitatively using NeuN antibody and determined by double-blinded quantification. Detailed calculations of mouse numbers are presented in the Vertebrate animals section. Control groups were injected with a non-specific CPR, anti-pan Aβ alone, and GFP. It is expected that each CPR has a differential effect on Aβ.
[0207] Based on these results the most effective anti-AβCPR agent can be pinpointed. To test whether CPRs are functional in a therapeutic paradigm, one or two of the most promising CPR from prevention study, and the appropriate controls, are administered intraocularly or into the tail vein into 4 month old CRND8 mice. At 4 months of age CRND8 mice have moderate levels of deposits, by 6 months they have significant amyloid accumulation. Amyloid burden and Aβ levels are assessed at 2 months post injection and compared to the non-specific CPR control group. These controls are designed to test whether non-specific activation of astrocytes is beneficial in targeting amyloid pathology. Additionally, control groups are injected with scFv's alone and GFP.
[0208] Given the above-described positive preliminary results and the demonstrated success in performing all the methods, experiments to assess the effect on prevention of aggregation and clearance of existing pathology are ongoing. CPRs activate astrocytes and microglia and it is possible that the non-specific CPR may have an effect on amyloid pathology. Nevertheless, the role of phagocytosis in amyloid clearance and the specific CPR domain may become better understood. Experiments are ongoing to optimize the CPRs of the disclosure to induce minimal off-target effects.
Example 2
[0209] CPRs May Bind AD or Tau when Expressed in Microglia or Monocytes and Alter the Proteinopathy in Ex Vivo Brain Slice Culture Models or In Vivo Following Transplantation of the CPR Expressing Microglia/Monocytes into the Brain of the Appropriate Proteinopathy Mouse Model.
[0210] This experiment evaluated whether the CPRs enhance microglial phagocytosis of amyloid plaques and tau aggregates. Multiple genetic association studies have identified numerous loci that harbor genes that encode proteins of known immune function that alter the risk of developing AD and other neurodegenerative proteinopathies (35). Microglial cells are the primary immune cells of the central nervous system and function as macrophages. They respond to foreign material or cellular debris by changing their morphology, becoming activated, migrating to the site of damage, clearing the foreign material and cellular debris through phagocytosis, and secreting signals to increase response to the insult (36). Activated microglia have been described as a common feature of many neurodegenerative diseases (37-39). To enhance microglial activity, microglia are transduced with CPRs (i.e., by AAV vectors encoding the CPRs). Transducing microglia in vivo remains a technical challenge, but a novel mutant capsid has been developed that transduces microglial cells in culture and ex vivo brain slices (FIGS. 9A and 9B). This allows testing of the approach of CPRs in a BSC model of model of tauopathy and to engineer microglial cells ex vivo and transplant into AD mouse model to increase phagocytic clearance of amyloid.
However, there are no objective evidences of administering astrocyte expressing chimeric receptor wherein the claimed method can treat, much less prevent any and all subject that include, but are not limited to, apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters having diagnosed with or at risk of developing any and all possible neurodegenerative disease, disorder or condition.
Chen et al (Science 391: 1006-1018, 2026; PTO 892) teaches that astrocytes are known to play essential roles in regulating neuronal activity and, like microglia, may contribute to synaptic pruning through their phagocytic function. However, owing to limitations of the current disease model, it remains unclear whether direct manipulation of astrocytes using our CAR system could lead to adverse effects from enhanced phagocytic activity. Despite clear reductions inamyloid pathology, behavioral outcomes—particularly in the late-stage Adu-Dectin1 cohort—did not show corresponding improvement. It re-mains unclear whether signaling from CAR intracellular domains, especially Dectin1, further amplifies activation of amyloid-primed glia, thereby disrupting synapse maintenance and neuronal function and offsetting the benefits of plaque reduction. Consistent with this possibility, CAR-A treatment in this cohort failed to rescue amyloid-associated synapse loss to the same extent observed in the early-intervention group. Together, these findings indicate that optimization of CAR-A signaling design, dosing strategies, and treatment timing will be essential to achieve cognitive benefit and underscore the need for systematic evaluation of potential side effects across multiple disease models and with more comprehensive behavioral testing. Future work should also assess how CAR-A compares with other gene- and cell-based approaches and whether combination strategies, including astrocyte-targeted metabolic therapies, can further enhance functional recovery, see p. 11, left col, in particular. Thus a skilled artisan would reasonably conclude that Applicant were not possession of the claimed invention at the time the application was filed.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
While the Federal Circuit has recognized that “the written description requirement can in some cases be satisfied by functional description,” it has made clear that “such functional description can be sufficient only if there is also a structure-function relationship known to those of ordinary skill in the art.” In re Wallach, 378 F.3d 1330, 1335 (Fed. Cir. 2004); see also, Enzo Biochem, Inc. v. Gen-Probe, Inc.,323 F.3d 956, 964 (Fed. Cir. 2002) (holding that the written description requirement would be satisfied “if the functional characteristic of preferential binding . . . were coupled with a disclosed correlation between that function and a structure that is sufficiently known or disclosed”); Amgen Inc. v. Sanofi, 782 F.3d 1367, 1378 (Fed. Cir. 2017) (holding that an “adequate written description must contain enough information about the actual makeup of the claimed products”). Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only (1) a chimeric receptor comprising:(i) an intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta, and (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the scFv comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3, wherein the intracellular phagocytic signaling domain comprises the amino acid sequence of SEQ ID NO: 11, 12, 15, 16, 18, 19, 24 or 25, (2) a modified astrocyte comprising said chimeric phagocytic receptor, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph.
Claims 1, 3-6, 13, 15, 17-18, 21, 41, 57 and 58 are 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 (1) a chimeric phagocytic receptor comprising:(i) an intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta, and (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the scFv comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3, wherein the intracellular phagocytic signaling domain comprises the amino acid sequence of SEQ ID NO: 11, 12, 15, 16, 18, 19, 24 or 25, (2) a modified astrocyte comprising said chimeric phagocytic receptor, wherein the modified cell is an astrocyte, does not reasonably provide enablement for any chimeric receptor as set forth in claims 1-6, 13, 15, 17-18, 21 for treating or preventing any subject diagnosed with any and all possible neurodegenerative disease as set forth in claims 57-58. 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.
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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (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. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompasses any chimeric receptor comprising:(i) an intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide, tau protein or a-synuclein protein, and (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the scFv comprises an amino acid sequence having at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% sequence identity to any of SEQ ID NOs: 1 (elected species).
Claim 3 encompasses any chimeric receptor comprising:(i) a first intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide, tau protein or a-synuclein protein, (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, and (iv) a second intracellular phagocytic signaling domain fused to the first intracellular phagocytic signaling domain.
Claim 4 encompasses the chimeric receptor of claim 2, wherein the scFv comprises an amino acid sequence having at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% sequence identity to any of SEQ ID NOs: 1-6.
Claim 5 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain comprises a hinge domain.
Claim 4 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain is covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain by one or more linkers.
Claim 5 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain comprises a hinge domain.
Claim 6 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain is covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain by one or more linkers.
Claim 13 encompasses the chimeric receptor of claim 1, wherein the first intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a MRC1 signaling domain, a MEGF10 signaling domain, a DAP12 signaling domain, a MERTK signaling domain, a FCERIy (or FCERG) signaling domain (elected species), a M6PR signaling domain, or a CLEC4L signaling domain.
Claim 15 encompasses the chimeric receptor of claim 3, wherein the first intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a MRC1 signaling domain, a MEGF10 signaling domain, a DAP12 signaling domain, a MERTK signaling domain, a FCERG signaling domain (elected species), a M6PR signaling domain, or a CLEC4L signaling domain; and the second intracellular phagocytic signaling domain comprises a TREM2 signaling domain, a MRC1 signaling domain (elected species), a MEGF10 signaling domain, a DAP12 signaling domain, a MERTK signaling domain, a FCERG signaling domain, a M6PR signaling domain, or a CLEC4L signaling domain.
Claim 17 encompasses the chimeric receptor of claim 1, wherein the chimeric receptor comprises an amino acid sequence having at least 85%, at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% sequence identity to any of SEQ ID NOs: 26-43 (SEQ ID NO: 28 as the elected species).
Claim 18 encompasses the chimeric receptor of claim 1, wherein the chimeric receptor comprises a second extracellular binding domain.
Claim 21 encompasses the chimeric receptor of claim 1, wherein the transmembrane domain is a TREM2 transmembrane domain, a MRC1 transmembrane domain, a MEGF10 transmembrane domain, a DAP12 transmembrane domain, a MERTK transmembrane domain, a CD8 transmembrane domain (elected specie), a M6PR transmembrane domain, or a CLEC4L transmembrane domain.
Claim 41 encompasses the chimeric receptor of claim 1, wherein the modified cell is an astrocyte.
Claim 57 encompasses a method of treating a subject is diagnosed with or at risk of developing a neurodegenerative disease, disorder, or condition, the method comprising: administering to the subject the modified cell of claim 41.
Claim 58 encompasses a method of preventing a neurodegenerative disease, disorder, or condition, the method comprising: administering to a subject the modified cell of any one of claim 41.
Regarding antibody, the specification defines as follow:
[0040] An “antibody” refers to an immunoglobulin molecule capable of specific or selective binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” encompasses not only intact (e.g., full-length) polyclonal or monoclonal antibodies, but also antigen-binding fragments thereof (such as Fab, Fab′, F(ab′)2, Fv), single chain (scFv), mutants thereof, fusion proteins comprising an antibody portion, humanized antibodies, chimeric antibodies, diabodies, linear antibodies, single chain antibodies, multispecific antibodies (e.g., bispecific antibodies) and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity or selectivity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. An antibody includes an antibody of any class, such as IgD, IgE, IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant domain of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
Regarding scFv antibody encompassed by the claimed chimeric receptor that binds to any amyloid beta peptide, the specification discloses just three scFv antibodies. Anti-Aβ9 scFv comprises the amino acid sequence of SEQ ID NO: 1, anti-Aβ2.1.3 scFv comprises the amino acid sequence of SEQ ID NO: 2, anti-Aβ scFv comprises the amino acid sequence of SEQ ID NO: 3.
However, the specification does not teach the structure, e.g., amino acid sequences of any and all possible scFv antibodies that bind to any amyloid beta peptide encompassed by the claimed chimeric receptor (claims 1, 3). The specification does not teach the structure, e.g., amino acid sequences of heavy chain variable domain and light chain variable domain of a sufficient number of species of the genus of scFvs encompassed by the claimed chimeric receptors. The specification does not teach the structure common to the members of the genus so the one of skill in the art can make and use the genus of the actual claimed chimeric receptor themselves for treating or preventing any and all neurodegenerative disease without undue experimentation.
Even assuming the scFv comprises any one of SEQ ID NO: 1-3, the specification does teach where and what amino acids within the full-length sequence of any one of SEQ ID NO: 1-3 to be substituted, deleted, added or a combination thereof such that the modified variant having at least 85%, 90% or 95% sequence identity to any one of SEQ ID NO: 1-3 still maintains antigen binding.
Regarding any intracellular phagocytic signaling domain, the specification discloses human FCERG comprises the amino acid sequence of SEQ ID NO: 11, human MRC1 comprises the amino acid sequence of SEQ ID NO: 12, mouse FCERG comprises the amino acid sequence of SEQ ID NO: 18, mouse MRC1 comprises the amino acid sequence of SEQ ID NO: 19, dual human FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 15, dual human MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 16, mouse dual FCERG-MRC1 comprises the amino acid sequence of SEQ ID NO: 24 and mouse MRC1-FCERG comprises the amino acid sequence of SEQ ID NO: 25.
Regarding chimeric phagocytic receptor (CPR), the specification discloses chimeric receptors that bind to amyloid beta and comprise the amino acid sequence of SEQ ID NO: 26-35, 42-43, see para. [0100].
However, the specification does not teach where and what amino acid within the full-length sequence of any one of SEQ ID NO: 26-35, 42 and 43 to be substituted, deleted, added or a combination thereof such that the modified chimeric receptor having at least 85%m 90% or 95% identity to any one of SEQ ID NO: 26-35, 42 and 43 maintains binding and effector functions (claim 17).
At the time the application was filed, it is well established in the art that even a single CDR substitution can disrupt antigen binding as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA Vol 79: 1979, 1982; PTO 892). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
Ito et al (FEBS Letters 309(1): 85-88, 1992; PTO 892) teaches substitution of histidine at various positions in an anti-lysozyme antibody. The L3A mutant contained a histidine in place of tyrosine in CDR3 of the light chain and the resulting mutant antibody lost its ability to bind to lysozyme antigen in an ELISA assay, see section spanning left and right column of page 86.
Piche-Nicholas et al MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Regarding treatment, the specification discloses:
[0035] The terms “ameliorate” and “treat” are used interchangeably and include both therapeutic and prophylactic treatment. Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a neurodegenerative disease or disorder described herein).
Thus the term treat encompasses prophylactic treatment or prevention.
Regarding “subject”, the specification discloses:
[0049] The term “subject” includes organisms which are capable of suffering from a disorder as described herein or who could otherwise benefit from the administration of a compound of the present disclosure, such as human and non-human animals. Preferred humans include human patients suffering from or prone to suffering from diseases or disorders as discussed above, as described herein. Mammalian species that may benefit from the disclosed methods of treatment include, but are not limited to, apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters. A “subject in need of treatment” includes a subject diagnosed, e.g., by a medical or veterinary professional, as suffering from or susceptible to a neurodegenerative disease, disorder or condition described herein.
The specification exemplifies:
Example 1
[0205] In vivo CPR prevention and clearance assessment. To evaluate the ability of CPR to prevent amyloid pathology, astrocytes are selectively transduced using rAAV-PHP.eB-GFAP-CPR and evaluate effects on amyloid pathology in CRND8 mice, a transgenic model that overexpresses mutant human amyloid protein precursor (APP) at levels approximately 5-fold higher than endogenous murine APP (see Chakrabarty, et al. Neuron 85, 519-533 (2015), incorporated herein by reference). For the prevention paradigm newborn CRND8 are injected with rAAV-PHP.eB-GFAP-CPR (with FCER1G, MRC1, MERTK, and CLEC4L with a non-specific CPR, anti-pan Aβ scFv alone, and GFP used as controls) (ICV, 4×10.sup.10 viral genomes/pup) and assess Aβ levels and plaque burden at 3 months. Each construct is delivered to 4-5 litters, resulting in −20 transgenic mice, of whom half will reach 3 months of age. Based on extensive experience with this strain, this cohort size allows to detect significant changes of 25% in amyloid levels. Small sub-cohorts on non-transgenic littermates at 4 weeks old are harvested to evaluate transduction and tropism.
[0206] At 3 months, the age at which substantial plaque formation is typically observed in these mice, one hemibrain is fixed and stained for amyloid immunoreactivity burden with anti-pan-Aβ antibody, Aβ5-biotin, and Thio-S. The other hemibrain is fractionated and Aβ levels are quantified by ELISA from RIPA-soluble fraction, SDS-soluble, and SDS-insoluble, formic acid-soluble fractions. Astrogliosis and microgliosis are evaluated using glial fibrillary acid protein (GFAP) and ionized calcium-binding molecule-1 (IBA-1) antibodies, respectively. Image analysis is done following scanning whole slides with the Aperio System and analysis of immunoreactivity burden by ImageScope program (Aperio, CA). Neuron counts in specific areas of the hippocampus and cortex where neurodegenerative may be observed by gross H&E analysis are also assessed quantitatively using NeuN antibody and determined by double-blinded quantification. Detailed calculations of mouse numbers are presented in the Vertebrate animals section. Control groups were injected with a non-specific CPR, anti-pan Aβ alone, and GFP. It is expected that each CPR has a differential effect on Aβ.
[0207] Based on these results the most effective anti-AβCPR agent can be pinpointed. To test whether CPRs are functional in a therapeutic paradigm, one or two of the most promising CPR from prevention study, and the appropriate controls, are administered intraocularly or into the tail vein into 4 month old CRND8 mice. At 4 months of age CRND8 mice have moderate levels of deposits, by 6 months they have significant amyloid accumulation. Amyloid burden and Aβ levels are assessed at 2 months post injection and compared to the non-specific CPR control group. These controls are designed to test whether non-specific activation of astrocytes is beneficial in targeting amyloid pathology. Additionally, control groups are injected with scFv's alone and GFP.
[0208] Given the above-described positive preliminary results and the demonstrated success in performing all the methods, experiments to assess the effect on prevention of aggregation and clearance of existing pathology are ongoing. CPRs activate astrocytes and microglia and it is possible that the non-specific CPR may have an effect on amyloid pathology. Nevertheless, the role of phagocytosis in amyloid clearance and the specific CPR domain may become better understood. Experiments are ongoing to optimize the CPRs of the disclosure to induce minimal off-target effects.
Example 2
[0209] CPRs May Bind AD or Tau when Expressed in Microglia or Monocytes and Alter the Proteinopathy in Ex Vivo Brain Slice Culture Models or In Vivo Following Transplantation of the CPR Expressing Microglia/Monocytes into the Brain of the Appropriate Proteinopathy Mouse Model.
[0210] This experiment evaluated whether the CPRs enhance microglial phagocytosis of amyloid plaques and tau aggregates. Multiple genetic association studies have identified numerous loci that harbor genes that encode proteins of known immune function that alter the risk of developing AD and other neurodegenerative proteinopathies (35). Microglial cells are the primary immune cells of the central nervous system and function as macrophages. They respond to foreign material or cellular debris by changing their morphology, becoming activated, migrating to the site of damage, clearing the foreign material and cellular debris through phagocytosis, and secreting signals to increase response to the insult (36). Activated microglia have been described as a common feature of many neurodegenerative diseases (37-39). To enhance microglial activity, microglia are transduced with CPRs (i.e., by AAV vectors encoding the CPRs). Transducing microglia in vivo remains a technical challenge, but a novel mutant capsid has been developed that transduces microglial cells in culture and ex vivo brain slices (FIGS. 9A and 9B). This allows testing of the approach of CPRs in a BSC model of model of tauopathy and to engineer microglial cells ex vivo and transplant into AD mouse model to increase phagocytic clearance of amyloid.
However, there are no objective evidences of administering astrocyte expressing chimeric receptor wherein the claimed method can treat, much less prevent any and all subject, including but are not limited to, apes; chimpanzees; orangutans; humans; monkeys; domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and other animals such as mice, rats, guinea pigs, and hamsters having diagnosed with or at risk of developing any and all possible neurodegenerative disease, disorder or condition.
Chen et al (Science 391: 1006-1018, 2016; PTO 892) teaches that astrocytes are known to play essential roles in regulating neuronal activity and, like microglia, may contribute to synaptic pruning through their phagocytic function. However, owing to limitations of the current disease model, it remains unclear whether direct manipulation of astrocytes using our CAR system could lead to adverse effects from enhanced phagocytic activity. Despite clear reductions inamyloid pathology, behavioral outcomes—particularly in the late-stage Adu-Dectin1 cohort—did not show corresponding improvement. It re-mains unclear whether signaling from CAR intracellular domains, especially Dectin1, further amplifies activation of amyloid-primed glia, thereby disrupting synapse maintenance and neuronal function and offsetting the benefits of plaque reduction. Consistent with this possibility, CAR-A treatment in this cohort failed to rescue amyloid-associated synapse loss to the same extent observed in the early-intervention group. Together, these findings indicate that optimization of CAR-A signaling design, dosing strategies, and treatment timing will be essential to achieve cognitive benefit and underscore the need for systematic evaluation of potential side effects across multiple disease models and with more comprehensive behavioral testing. Future work should also assess how CAR-A compares with other gene- and cell-based approaches and whether combination strategies, including astrocyte-targeted metabolic therapies, can further enhance functional recovery, see p. 11, left col, in particular.
As such, it would take undue trials and errors to practice the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 3-6, 13, 18 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over US20200345774 (Getts hereafter, published November 5, 2020, claimed earliest priority to 62/841,190, filed April 30, 2019, PTO 892) in view of US20100104577 (Golde hereafter, published April 29, 2010; PTO 892) and U.S. Patent No. 12,344,662 (filed February 11, 2019, claimed earliest priority to 62/628,632, filed February 9, 2018; PTO 892).
Claim 1 recites a chimeric receptor comprising:(i) an intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide, tau protein or a-synuclein protein, and (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, wherein the scFv comprises an amino acid sequence having at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% sequence identity to any of SEQ ID NO: 1 (elected species).
Claim 3 recites the chimeric receptor comprising:(i) a first intracellular phagocytic signaling domain, (ii) an extracellular binding domain comprising a single-chain variable antibody fragment (scFv) having affinity for an amyloid beta peptide, tau protein or a-synuclein protein, (iii) a transmembrane domain positioned between and covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain, and (iv) a second intracellular phagocytic signaling domain fused to the first intracellular phagocytic signaling domain.
Claim 4 recites the chimeric receptor of claim 2, wherein the scFv comprises an amino acid sequence having at least 98% at least 99% sequence identity to any of SEQ ID NO: 1.
Claim 5 recites the chimeric receptor of claim 1, wherein the transmembrane domain comprises a hinge domain.
Claim 6 recites the chimeric receptor of claim 1, wherein the transmembrane domain is covalently linked to the intracellular phagocytic signaling domain and the extracellular binding domain by one or more linkers.
Claim 13 recites the chimeric receptor of claim 1, wherein the first intracellular phagocytic signaling domain comprises a FCERIγ (or FCERG) signaling domain (elected species).
Claim 18 recites the chimeric receptor of claim 1, wherein the chimeric receptor comprises a second extracellular binding domain.
Claim 21 recites the chimeric receptor of claim 1, wherein the transmembrane domain is a CD8 transmembrane domain (elected specie).
Regarding claims 1, 3-5, 21, Getts teaches a chimeric phagocytic receptor comprising an extracellular domain (ECD) that binds to CD5 (see para. [0325]), a hinge region of a CD8 receptor (see para. [0327]), a CD8 transmembrane region (see para. [0328]), one or more intracellular domains (ICD), e.g., phagocytic signaling domains, e.g., FcγR, FcαR or FcεR, see para. [0039], [0075], [0076], [0078], [0329], FIG 6A below.
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Getts teaches that targeting cell, e.g., human primary macrophage cells expressing phagocytic receptor is expected to enhanced phagocytosis of such cells thereby clearing diseased cells, see para. [0008] to [0010], [0027], [0029].
Getts does not teach the single-chain antibody (scFv) having affinity for an amyloid beta peptide as per claims 1 and 3, wherein the scFv comprises an amino acid sequence having at least 98% identity to SEQ ID NO: 1 as per claims 1 and 4, and intracellular phagocytic signaling domain comprises a FcεRIγ (FCERG) or DAP12 as per claim 13.
However, Golde teaches various scFv having affinity for an amyloid beta peptide or epitope, e.g., scFv40.1 or scFv42.2 or scFv9, see entire document, para. [0008] to [0010], in particular. The reference scFv9 comprises the amino acid sequence of SEQ ID NO: 4, which is 98.7% identical to the claimed SEQ ID NO: 1, see sequence alignment in particular.
Query Match 98.7%; Score 1300; Length 246;
Best Local Similarity 98.8%;
Matches 243; Conservative 1; Mismatches 2; Indels 0; Gaps 0;
Qy 1 QVTLKESGPGILQPSQTLSLTCSFSGFSLNTFGMGVSWIRQPSGKGLEWLAHIFWDDDKH 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVTLKESGPGILQPSQTLSLTCSFSGFSLNTFGMGVSWIRQPSGKGLEWLAHIFWDDDKH 60
Qy 61 YNPSLKSRLTISKDTSNNQVFLKITTVDTADTATYYCVRYGFDGFPYWGQGTLVTVSAGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YNPSLKSRLTISKDTSNNQVFLKITTVDTADTATYYCVRYGFDGFPYWGQGTLVTVSAGG 120
Qy 121 GGSGGGGSGGGGSDVVMTQTPLSLPVSLGDQASISCRSNQSLVHSNGNTYLHWYLQKPGQ 180
|||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||
Db 121 GGSGGGGSGGGGSDVVMTQTPLSLPVSLGDQASIXCRSNQSLVHSNGNTYLHWYLQKPGQ 180
Qy 181 SPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGFYFCSQSTRVPWTFGGGT 240
||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||
Db 181 SPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGFYFYSQSTRVPWTFGGGT 240
Qy 241 KLELKR 246
|||:||
Db 241 KLEIKR 246
Specific Monoclonal Antibodies Attenuate Amyloid Deposition in an Alzheimer's Disease Mouse Model, see Example 1, in particular. Ab9 and Ab3 treatment resulted in significant reductions in both FA A.beta.40 and FA A.beta.42 levels, see para. [0062], in particular.
Likewise, the ‘662 patent teaches chimeric antigen receptor comprising scFv that binds to aberrant amyloid beta for treating a neurodegenerative disease, see entire document, col. 73, line 3-16, col. 12, in particular. Example of scFv antibody DG01 that has affinity for amyloid beta comprises the amino acid sequence of SEQ ID NO:1, which is 99.6% sequence identity the claimed SEQ ID NO: 3 as per claims 1 and 4, see col. 4, lines 53-54, col. 9, see sequence alignment below:
OTHER INFORMATION: DG01 SCFV
Query Match 96.4%; Score 1283.5; Length 266;
Best Local Similarity 99.6%;
Matches 246; Conservative 0; Mismatches 0; Indels 1; Gaps 1;
Qy 2 QVQLVESGGGVVQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWVAVIWFDGTKKYY 61
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 20 QVQLVESGGGVVQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWVAVIWFDGTKKYY 79
Qy 62 TDSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDRGIGARRGPYYMDVWGKGTTV 121
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 80 TDSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDRGIGARRGPYYMDVWGKGTTV 139
Qy 122 TVSS-GGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKP 180
|||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 140 TVSSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKP 199
Qy 181 GKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 200 GKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGG 259
Qy 241 GTKVEIK 247
|||||||
Db 260 GTKVEIK 266
The ‘662 patent teaches that chimeric antigen receptors (CARs) may comprise a hinge sequence between the antigen binding (AB) domain and a transmembrane (TM) domain. One of the ordinary skill in the art will appreciate that a hinge sequence is a short sequence of amino acids that facilitates flexibility, a transmembrane domain (TM domain), one or more intracellular signaling domain (ICS). Typically, the TM domain denotes a single transmembrane α helix of a transmembrane protein, also known as an integral protein.
Examples of ICS include FcεRI, DAP10, and DAP12, see col. 29, lines 5-6, col. 31, line 41-46, col. 51, line 11-17, in particular.
Regarding claim 6, the ‘662 patent teaches various flexible linker, e.g., Gly/Ser linker, see col. 29, line 28-40.
Regarding claim 13, the ‘662 patent teaches examples of cytoplasmic signaling sequence include, but not limited to FCER1G (col. 31, line 45), or DAP12, see col. 29, lines 5-6, col. 31, line 41-46, col. 51, line 11-17, in particular.
Regarding claim 18, the ‘662 patent teaches chimeric receptor comprises one or more extracellular binding domain as per claim 18 (see col. 24, lines 39-42).
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Getts, Golde and the ‘662 patent by substituting the scFv in the chimeric phagocytic receptor of Getts for Golde’s scFv9 that binds to amyloid beta peptide or the ‘662 patent’s scFv antibody DG01 that has affinity for amyloid beta wherein the chimeric phagocytosis receptor having one or more intracellular phagocytic signaling domain such as FCER1G and/or DAP12 as taught by the ‘662 patent to arrive at the claimed invention with a reasonable expectation success, i.e., targeting chimeric phagocytic receptor expressing cells to aberrant amyloid beta in order to clear diseased aberrant amyloid beta.
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to modify the chimeric receptor of Getts in view of Golde et al and the ‘662 patent because Golde teaches chimeric antigen receptor comprising scFv that binds to aberrant amyloid beta is useful for treating a neurodegenerative disease, see entire document, col. 73, line 3-16, col. 12) and the ‘662 patent teaches that human amyloid beta, amyloid-beta 1-42 is associated with neurodegenerative disease and targeting chimeric antigen receptor to aberrant amyloid beta is useful for treating a neurodegenerative disease (see entire document, col. 10, line 60-67 to col. 11, line 18). Likewise, Getts teaches that targeting cell expressing phagocytic receptor is expected to enhanced phagocytosis of such cells thereby clearing aberrant amyloid beta (see para. [0008] to [0010]). One of ordinary skill in the art would have been motivated to do so because Golde teaches scFv9 attenuate A.beta. deposition in old CRND8 mice, see para. [0025].
One would have been motivated, with a reasonable expectation of success to do this for targeting cell expressing chimeric phagocytic receptor to engulf aberrant amyloid beta because Golde teaches scFv9 is specific for A beta and attenuate A.beta. deposition in old CRND8 mice, see para. [0025].
One of ordinary skill in the art would have been motivated to do so because the ‘662 patent teaches that chimeric antigen receptor (CAR) which comprises scFv that targets at least one aberrant protein, e.g., Aβ peptides is useful for treating neurodegenerative disease or condition (see Summary, in particular) and Getts teaches that cell expressing chimeric phagocytic receptor is able to clear disease cells.
Further, the simple substitution of one known element for another to obtain predictable results is one of the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143 as a rationale supporting obviousness.
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Finally, applying known technique of making chimeric phagocytic receptor to a known product would be ready for making another chimeric phagocytic receptor to a known product in the same way.
“The test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over US20200345774 (Getts hereafter, published November 5, 2020, claimed earliest priority to 62/841,190, filed April 30, 2019, PTO 892) in view of US20100104577 (Golde hereafter, published April 29, 2010; PTO 892) and U.S. Patent No. 12,344,662 (filed February 11, 2019, claimed earliest priority to 62/628,632, filed February 9, 2018; PTO 892) as applied to claims 1, 3-6, 13, 18, and 21 mentioned above and further in view of US20200055917 (Corey hereafter, published February 20, 2020; PTO 892).
The combine teachings of Getts, Golde and the ‘662 patent have been discussed supra.
The references above do not teach that the chimeric receptor wherein the second intracellular phagocytic signaling domain comprises a MRC1 signaling domain as per claim 15.
However, Corey teaches chimeric engulfment receptor (aka chimeric phagocytic receptor) to remove apoptotic cells without causing damage to the surrounding tissues or inducing a pro-inflammatory immune response, see entire document, para. [0004]. Corey teaches that the chimeric engulfment receptors (“CER” in the singular and “CERs” in the plural), e.g., scFv that binds to phosphatidylserine (PtdSer), para. 0154], [0158], [0163], reference claims 1-2), a transmembrane domain, and an intracellular engulfment signaling domain, see para. [0006], [0148], [0176], reference claims 1-2, 4-5, 8, 12. Examples of transmembrane domain is a CD8a transmembrane domain, or a MRC1 transmembrane domain, see para. [0232], [0233], in particular. Examples of engulfment signaling domains include MRC1 (SEQ ID NO: 56, para. [0223]), FcεR1, DAP12 , see para. [0009], [0229], reference claim 12, in particular. The one or more of the specific signaling domains include MRC1, FcεR1, DAP12, MERTK, see para. [0229], reference claim 20, in particular. Corey teaches that cells genetically modified to express chimeric engulfment receptor (CER) that targets a pro-engulfment marker associated with dead, dying, damaged, infected, or necrotic cells, see para. [0010]. The target cells may be a tumor cell, a misfold protein associated with a neurodegenerative disease, e.g., Alzheimer’s disease, see para. [0151]. The aberrant accumulation of proteins such as amyloid-β or tau in n Alzheimer's disease; α-synuclein in Parkinson's disease (PD), see para. [0322]. Examples of cells include CD8.sup.+ or CD4.sup.+ T cells, Natural Killer Cells, Natural Killer T cells, B cells, lymphoid precursor cells, antigen presenting cells, dendritic cells, Langerhans cells, myeloid precursor cells, mature myeloid cells, including subsets thereof, or any combination thereof, see para. [0323].
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the intracellular signaling domains FcεRI of Getts, Golde and the ‘662 patent with any one of Corey’s engulfment signaling domain comprises an MRC1 signaling domain to arrive at the claimed chimeric receptor comprises a first intracellular domain FcεRI and a second intracellular domain MRC1 in order to activate different phagocytic signaling pathways.
One of ordinary skill in the art would have been motivated to do so because Corey teaches that the cell expressing chimeric phagocytic receptor (CERs) may be advantageous as host cells, including trafficking to sites, capable of internalizing and self-renewing (persist for life), see para. [0299] and
Golde teaches chimeric antigen receptor comprising scFv that binds to aberrant amyloid beta is useful for targeting cells expressing chimeric phagocytic receptor (CERs) to human amyloid beta, amyloid-beta 1-42 that is associated with neurodegenerative disease and Getts teaches that targeting cell expressing phagocytic receptor is expected to enhanced phagocytosis of such cells thereby clearing aberrant amyloid beta (see para. [0008] to [0010]).
Further, the simple substitution of one known element for another to obtain predictable results is one of the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143 as a rationale supporting obviousness.
“The test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claims 41, 57 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over US20200345774 (Getts hereafter, published November 5, 2020, claimed earliest priority to 62/841,190, filed April 30, 2019, PTO 892) in view of US20100104577 (Golde hereafter, published April 29, 2010; PTO 892) and U.S. Patent No. 12,344,662 (filed February 11, 2019, claimed earliest priority to 62/628,632, filed February 9, 2018; PTO 892) as applied to claims 1, 3-6, 13, 18, and 21 mentioned above and further in view of Rosenthal (US20180186855, published July 5, 2018; PTO 892).
The combine teachings of Getts, Golde and the ‘662 patent have been discussed supra.
The references above do not teach that a modified cell comprising the chimeric antigen receptor of claim 1 wherein the cell is an astrocyte as per claim 41, a method of treating a subject is diagnosed with or at risk of developing a neurodegenerative disease, disorder, or condition, the method comprising: administering to the subject the modified astrocyte and a method of preventing a neurodegenerative disease, disorder, or condition, the method comprising: administering to a subject the modified astrocyte as per claim 58.
However, Rosenthal teaches a chimeric receptor comprising an extracellular binding domain, e.g., anti-amyloid beta chain-chain variable fragment (scFv) domain (see para. [0009], [0017]), a CD8 hinge domain, a CD8 transmembrane domain, an intracellular signaling domain, e.g., a common FcR gamma (FCERIG, para. [0102]), DAP12 intracellular domain, see para. [0009], [0102], [0104].
Regarding cells, Rosenthal teaches that cells include astrocytes, see para. [0009], [0014], [0018]. Rosenthal teaches that signaling through DAP12 or TCR3Zeta receptor ITAM intracellular domains leads to downstream signaling events such as Syk kinase activation, which promotes survival, functionality, phagocytosis, and proliferation in cells, e.g., astrocytes, see para. [0105]. TREM2, an endogenous receptor that signals through DAP12, is protective in human and in mouse models of Alzheimer's disease and multiple sclerosis, see para. [0105].
Regarding claims 57 and 58, Rosenthal teaches administering astrocytes containing the chimeric receptor (para. [0167], [0286]) to an individual diagnosed with dementia induces clearance or phagocytosis of disease-associated protein or cells, see para. [0286], thereby treating or preventing neurodegenerative disease, e.g., Alzheimer’s disease, dementia, see para. [0290] to [0300].
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to substitute the cell that expressing the chimeric receptor of Getts, Golde and the ‘662 patent for another, e.g., astrocyte as taught by Rosenthal to arrive at the claimed invention with a reasonable expectation of success, e.g., a astrocytes expressing a chimeric engulfment receptor (CER) comprising a single chain chimeric protein, the single chain chimeric protein comprising: an extracellular domain comprising a scFv that binds to a target antigen, e.g., beta amyloid; a CD8 hinge, a CD8 transmembrane domain, a first engulfment signaling domain, e.g., FcεR1 or MRC1 signaling domain and a second engulfment signaling domain, e.g., FcεR1 and/or MRC1.
One would have been motivated, with a reasonable expectation of success to do this for targeting astrocyte cell expressing chimeric phagocytic receptor to engulf aberrant amyloid beta because Rosenthal teaches administering astrocytes containing the chimeric receptor (para. [0167], [0286]) to an individual diagnosed with dementia induces clearance or phagocytosis of disease-associated protein or cells, see para. [0286], thereby treating or preventing neurodegenerative disease, e.g., Alzheimer’s disease, dementia, see para. [0290] to [0300].
Further, the simple substitution of one known element for another to obtain predictable results is one of the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143 as a rationale supporting obviousness.
“The test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Allowable Subject Matter
SEQ ID NO: 2, 11-12, 15-16, 24-35, 42-43 are free of prior art.
Conclusion
No claim is allowed.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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