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 .
Response to Amendment
The amendment filed 10 September 2025 is acknowledged. Claims 34 and 36 are amended.
Claim Status
Claims 1-34, 36, 46-47, 49-81, and 97-98 are pending. Claims 1-33, 49-81, and 97-98 are withdrawn pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species of invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8 November 2023. Claims 34, 36, 46, and 47 are pending and under examination in the instant office action.
Withdrawal of Objections
The objection to the drawings because Fig. 9, Fig. 14C (left), Fig. 15B, Figs. 19-21, Fig. 22B, Fig. 23A, and Fig. 24A-B are blurry such that the labels are unreadable is withdrawn in view of the replacement drawings.
The objection to the drawings because Figs. 1, 3, 4C, 4G, 8B, 9D, 9E, 9F, 13A, 14D, 14E, 15C, 16C, 17C, 17E, 17G, and 22A contain legends with indistinguishable shades of grey is withdrawn in view of the approved petition for color drawings.
Withdrawal of Rejections
The rejections of claims 34, 46, and 47 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the amendment to the claims.
Priority
Applicant’s claim under 35 U.S.C. §§ 119(e) and/or 120, 121, or 365(c) for benefit of the filing dates of earlier filed applications is acknowledged.
However, claims 34, 36, 46, and 47 do not properly benefit under §§ 119 and/or 120 by the earlier filing dates of the priority documents claimed, since those claims are rejected under 35 U.S.C. § 112(a) as lacking adequate written description and a sufficiently enabling disclosure.
To receive benefit of the earlier filing date under §§ 119 and/or 120, the later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application); the disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. § 112(a). See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). See M.P.E.P. § 201.11.
Accordingly, the effective filing date of the claims is deemed the filing date of the instant application, namely January 14, 2021.
Claim Rejections - 35 USC § 112(b)- Maintained, changes necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 36 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 36 is indefinite for the recitation of “A method of inhibiting neurotoxicity induced by CAR T cell that target cells that express CD19”. This is indefinite because it is unclear how the subject that has neurotoxicity induced by CAR T cells exists without prior administration of CAR T cells that induced neurotoxicity. It is unclear how the subject would be identified as in need of a method of inhibiting CAR T cell induced neurotoxicity, or to what level of neurotoxicity would indicate neurotoxicity was inhibited or not. The applicant is requested to clarify whether the metes and bounds of the claim are directed to inhibiting existing CAR T induced neurotoxicity in a patient that has previously received traditional anti-CD19 CAR T cells. If not, the examiner suggests rephrasing the method to clarify the inhibition of neurotoxicity and the scope of the subjects in need thereof.
Claim Rejections - 35 USC § 112(a)- Written Description- Maintained, Modifications necessitated by amendment
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 34, 36, 46, and 47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the claimed genus
Regarding claims 34 and 36, the claims are directed towards a method of treating cancer or a method of inhibiting CAR T cell-induced neurotoxicity in a subject in need thereof comprising administering CD4+ or CD8+ T cells comprising a CAR which binds to an epitope of human CD19 comprising the amino acid sequence of SEQ ID NO: 30 and an iCAR which binds to an antigen expressed on the surface of pericytes in the human subject, wherein the antigen is CD146.
Therefore the, scope of the claims includes:
Any modified CD4+ or CD8+ T cell comprising:
Any CAR comprising:
Any antigen binding domain binding to SEQ ID NO: 30
A CD8 transmembrane domain
And a CD3zeta signaling domain
Any iCAR comprising:
Any antigen binding domain specific for an antigen comprising CD146 expressed on a human pericyte in the human subject
A PD-1 transmembrane domain
Any inhibitory signaling domain of PD-1 wherein the inhibitory signaling domain provides an inhibitory signal to the modified T cell upon engagement of the iCAR with its target to inhibit or suppress any activity of the modified T cell.
Further regarding claim 36, the claims include any method of inhibiting neurotoxicity induced by CAR T cells that express CD19, and therefore would include inhibiting CAR T cell-induced neurotoxicity in a subject who has already received a prior administration of anti-CD19 CAR T cells which did not comprise the iCAR.
State of the Relevant Art
Regarding inhibitory CARs (iCARs), some are known in the art. Fedorov et. al. (Of record) created iCARs with an anti-PSMA scFv fused to a CTLA-4 or PD-1 transmembrane domain and cytoplasmic tail, which were able to reduce the cytokine production and proliferation of an anti-CD19 second generation CAR with a CD28 co-stimulatory/CD3zeta intracellular signaling domain in response to CD19+PSMA+ target cells compared to CD19+ target cells (Fig. 5, Fig. 6). Fedorov teaches “In applying the iCAR strategy in a clinical setting, the functionality of every iCAR will need to be optimized on the basis of receptor affinity, receptor expression level (that is, promoter strength), and selection of suitable target antigens based, in part, on their expression level. These will also need to be balanced against the activating receptor to achieve inhibition at off-target sites. In the case of CAR-targeted therapy, an optimized CAR/ iCAR ratio could be achieved through careful vector design” (Discussion, para 6). Hamburger A. et. al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020 Dec;128:298-310. doi: 10.1016/j.molimm.2020.09.012. Epub 2020 Oct 1. PMID: 33012527 shows that although pieces of the “blocker” (equivalent to iCAR) and activator (including CARs and TCRs) pairs were modular and “robust”, there were changes in both activation and inhibition based on the antigen binding module of both the CAR and iCAR and the inhibitory domain and based on antigen concentrations. In regards to PD-1-mediated inhibition of CAR signaling and CAR-T cells, Cherkassky L, et. al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016 Aug 1;126(8):3130-44. doi: 10.1172/JCI83092. Epub 2016 Jul 25. PMID: 27454297; PMCID: PMC4966328 teach CAR-T cells comprising an anti-MSLN scFv CAR with a CD28 co-stimulatory domain showed increased sensitivity to endogenous PD-1 inhibition compared to CAR T cells with a 4-1BB based co-stimulatory domain based on T cell persistence, cytotoxic ability, and cytokine secretion (abstract). Traditional activating CARs have also been shown to have both ligand-dependent and ligand-independent tonic signaling which is dependent on the specific antigen binding domain, hinge, transmembrane domain, intracellular signaling domain, and other specific structural components of the CAR peptide (See: Ajina A, Maher J. Strategies to Address Chimeric Antigen Receptor Tonic Signaling. Mol Cancer Ther. 2018 Sep;17(9):1795-1815. doi: 10.1158/1535-7163.MCT-17-1097. PMID: 30181329; PMCID: PMC6130819). These specific structures would be essential to the method of treating comprising a CAR and an iCAR and to the degree of activating and inhibitory signal needed to successfully treat cancer or reduce neurotoxicity compared to a CAR-T cell that does not comprise the iCAR.
Here, it is noted that no one element of the conventional CAR, typically comprising an extracellular ligand binding domain, a spacer, a transmembrane domain, and an intracellular (cytoplasmic) signaling domain has been found to be purely structural (Reviewed in: Feins et. al., of record). Even the transmembrane domain, which might at once been regarded to have played only a structural role, has been found to impart particular functional properties upon the CAR. Bridgeman et al. (Of Record, J. Immunol. 2010 Jun 15; 184 (12): 6938-49) found, for example, that CARs containing the CD3z transmembrane domain can form a complex with the endogenous TCR that may be beneficial for optimal T cell activation, a property that could be abolished by altering the structure of the transmembrane domain by amino acid substitution (see entire document; e.g., the abstract). It is therefore reasonable to question whether a CAR/iCAR pair such as that to which claim 34, for example, must have a specific structure to have the requisite degree of activation and inhibition required by the method.
Turning again to claim 36, which is drawn to a method of inhibiting neurotoxicity induced by CAR T cell that targets cells that express CD19, wherein the CAR T cell targets cells that express CD19, it must be questioned what this means before it might ever be fairly concluded that such an invention is actually described by the application. As disclosed at page 43 of the specification, one way of measuring neurotoxicity is by assessing the clinical manifestations of the symptoms thereof, but must each and every symptom or potential indication of the “neurotoxicity” be eliminated or prevented from ever occurring? It is not clear, but how might the incidence of one sign or symptom of the “neurotoxicity” resulting from the administration of the CD19-specific CAR T cell therapy, if that were the case, ever be distinguished from the incidence of the same or another sign or symptom resulting from a different cause? Notably, the specification discloses that symptoms of neurotoxicity include tingling or numbness in limbs, loss of memory, imbalance, and flu-like symptoms (e.g., fever). How is it reasonably expected that the method might ever be used to prevent any and all signs and symptoms of “neurotoxicity”, especially when so many of them might be the result or consequence of other conditions, infections, disorders, and diseases? While it is not clear what it actually means to inhibit the “neurotoxicity” that occurs in subjects receiving CD19-specific CAR T cell therapy, if that were the case, it does not appear likely that the objective has ever been achieved or ever will. This seems especially true in light of the teachings of Fedorov et al. (Of record). Fedorov et al. appears to be among the first of publications describing the concept of the dual CAR T cell, which expresses a “therapeutic” CAR, as well as an inhibitory CAR (iCAR), which functions to minimize “on-target, off-tumor” adverse side effects (see entire document; e.g., the abstract). Fedorov et al. teaches “[in] most of our analyses, the iCAR reduced T cell function but did not abrogate it, rarely exceeding 90% inhibition in any assay” (page 8). Such a finding suggests that it would be essential to determine the degree of iCAR reduction of T cell function needed to translate into inhibition of neurotoxicity. As Fedorov et al. teaches, the level of expression of the iCAR is critical (page 7). As discussed above, Fedorov et al. teaches, “[in] applying the iCAR strategy in a clinical setting, the functionality of every iCAR will need to be optimized on the basis of receptor affinity, receptor expression level (that is, promoter strength), and selection of suitable target antigens based, in part, on their expression level” and that all of these factors “will also need to be balanced against the activating receptor to achieve inhibition at off-target sites” (page 8). All of these factors suggest that in order to show possession of this genus of invention, the specific structures would need to be defined. Additionally, if the method is specifically to inhibit CAR T-cell induced neurotoxicity, would it be sufficient to completely cripple the activation of the T cell in order to perform the method? Administration of a T cell comprising, for example, an iCAR with a constitutively active PD-1 intracellular signaling domain would potentially dampen the activating signal of the T cell in order to inhibit CAR T cell induced neurotoxicity, but that would seem to also thwart the therapeutic purpose of the invention.
Even regarding only antibody-based antigen binding domains, it is well established in the art that the formation of an intact antigen-binding site in an antibody requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Additionally, even if antigen were sufficient to define an entire genus of CARs or iCARs, the specific nature of the paratope/epitope interaction of the CAR and iCAR would be expected to change the nature of the activating and inhibitory signals, and thus the functionality of the method. Although not prior art, Partin AC, et. al. Geometric parameters that affect the behavior of logic-gated CAR T cells. Front Immunol. 2024 Jan 26;15:1304765. doi: 10.3389/fimmu.2024.1304765. PMID: 38343543; PMCID: PMC10853413 teach that antigen height is a functional parameter in the ability of an iCAR to decrease the activating signal of an anti-CD19 CAR (Fig. 1) and show this to be true of between epitopes targeted by the same anti-MSLN CAR, where very little inhibition was shown for a distal epitope (Fig. 2). Thus, the Applicant would not be expected to possess the entire genus of methods comprising any T cell comprising an anti-human CD19 CAR and an anti-human CD146 iCAR as claimed.
Summary of Species disclosed in the original specification
The instant specification does not contain any specific species of methods of treating cancer or inhibiting neurotoxicity by administering a T cell comprising a CAR and an iCAR to a subject. Although it is appreciated how much discovery effort has gone into identifying CD146 as a candidate for an iCAR antigen to be coupled with a CAR in order to reduce CD19-dependent neurotoxicity, the specification is clear that the inventions are candidates (Fig. 25). There are no specific scFvs targeting CD19 or CD146, or their use in pairs, identified in the specification. Although Fig. 25 suggests “4 ITIM candidates” and an activating CD19 CAR, the specific structures of theses CAR and iCAR pairs are not disclosed. Additionally, there is no data in the specification that suggests the activating or inhibitory behavior of T cells comprising the CAR and the iCAR has been tested.
Turning to address the invention according to claim 36, which again is a method intended for use in inhibiting neurotoxicity, because the claims do not recite the administration of a CAR T cell that induces neurotoxicity to the subject before the administration of the modified T cell to the subject, it is not understood how or why the objective of the claimed invention might ever be met. Certainly, the modified T cell administered to the subject cannot be said to both cause the induction of CAR T cell-induced neurotoxicity and inhibit CAR T cell-induced neurotoxicity.1 So, then, how is it that the invention is to be practiced to achieve the claimed objective? Must the subject be given a CAR T cell that induces neurotoxicity, perhaps before or during the administration to the subject of the modified T cell? As noted in the preceding Office action, it would seem very unlikely that the invention should ever be practiced by inducing CAR T cell-induced neurotoxicity, only to permit its use as intended (i.e., to inhibit CAR T cell-induced neurotoxicity).
Of a related note, the modified T cell to which the claims are directed need not be an autologous T cell isolated from the subject and may not be an allogenic T cell isolated from an individual other than the subject, but of the same species. It is only according to claim 46 and T cell is necessarily autologous; and it is only according to claim 47 that it is allogeneic. Therefore, it stands to reason that the T cell according to claim 34, for example, might not be a cell that was isolated from the subject or even an individual of the same species. Yet, it is very unlikely that a non-human (e.g., cat or dog) T cell, for example, might ever be used in practicing the claimed invention to treat (or prevent) cancer or inhibit CAR T cell-induced neurotoxicity in a human subject. There are a great number of reasons why, but to name one, the cell will most likely be rejected (eliminated) by the subject’s immune system and even if it weren’t, it cannot be presumed that the T cell will function to eliminate cancer cells in the subject.
In regards to types antigen binding domains disclosed, although scFvs are specifically mentioned, the claims are so broad as to allow and antigen binding domain of any material (e.g., a polypeptide or a portion thereof), which somehow acts to bind to an antigen (e.g., CD146). It might, for example, be an organic compound that that mimics an antibody by binding to specific antigens (polypeptides), but which are wholly unrelated in structural terms to an antibody (e.g., an Anticalin™ or an Affimer™); or, as another example, it might be a polypeptide or a portion thereof (e.g., the extracellular domain), which acts as a receptor for the antigen. The point is that the natures of “antigen-binding domains” of the CAR and the iCAR to which the claims are directed are very much undefined. Because the claims are drawn to such materially and structurally disparate materials, there is no correlation between any one particularly identifying material and/or structural feature that is shared by at least most members of the genus of “antigen-binding domains” and their common ability to bind to an antigen (i.e., presumably CD19, in the case of the CAR, or CD146, in the case of the iCAR). For this reason, it is submitted that the skilled artisan could not immediately envisage, recognize, or distinguish at least a substantial number of the “antigen-binding domains” of which the CAR and the iCAR may be constructed and used in practicing the claimed inventions to achieve the claimed objectives. As a consequence, it is further submitted that the specification would not reasonably convey Applicant’s possession of the claimed inventions as of the filing date of the application, so as to satisfy the written description requirement.
Summary
In deciding The Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997), the Federal Circuit held that a generic statement that defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. By analogy, a generic statement that defines a genus of modified T cells comprising, for example, an antigen-binding domain by only the common ability of the antigen binding domain to bind to CD19 does not serve to adequately describe the genus as whole. The Court indicated that while applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a precise definition of a representative number of members of the genus, such as by reciting the structure, formula, chemical name, or physical properties of those members, rather than by merely reciting a wish for, or even a plan for obtaining a genus of molecules having a particular functional property. The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of genus must be capable of doing, not of the substance and structure of the members.
To an extent, it is submitted that the claims are drawn to a method that uses a product (i.e.., “a modified T cell), which is analogous to the proverbial “black box”, which causes an effect, but where the inner workings and mechanisms by it actually does so are left to one’s imagination. Even if perhaps a skilled artisan could envisage one means by which CD4+ or CD8+ T cell comprising “a CAR” and “an iCAR”, which satisfy the requirements of the claims, could be produced, another skilled artisan might just as readily envision a second, different means by which the cell could be produced. The question that should then be asked is what is the process or means by which the cells, which is actually described by this application, are produced because it is likely that process or means that would be recognized as having been in Applicant’s possession at the time the application was filed, and no others, and especially not any other process or means that might be the product of another’s ingenuity and creativity.
In summary, it is submitted that in this case, since the claims are so broad, and the disclosure is so comparably limited, any alleged conception has no more specificity than simply a wish to know the identity of any material with that requisite biological properties, which can be used to practice the claimed methods, so as to achieve the claimed objectives. In such instances, the alleged conception fails not merely because the field is unpredictable or because of the general uncertainty surrounding experimental sciences, but because the conception is incomplete due to factual uncertainty that undermines the specificity of the inventor’s idea of the invention. Burroughs Wellcome Co. v. Barr Laboratories Inc., 40 F.3d 1223, 1229, 32 USPQ2d 1915, 1920 (Fed. Cir. 1994). Reduction to practice in effect provides the only evidence to corroborate conception (and therefore possession) of the invention.
Lastly, since the claims are not necessarily limited to known materials having the properties of the claimed “modified T cell”, but rather to such material that might be identified, given the bid set forth in the instant disclosure to do so, it is noted that one cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483 (Bd. Pat. App. & Int. 1993).
Dependent claims are rejected for failing to resolved the written description issues as described for claim 34 above.
Response to Arguments
Applicant’s arguments dated 10 September 2025 have been fully considered but are not persuasive.
Applicant argues that the Examiner’s rejection focuses on the various domains of the specified CAR and iCAR but overlooks the invention taken as a whole. MPEP 2163 states, “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 (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or 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 the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).")” (emphasis is the examiner’s). As described in the written description rejection above, the Applicant has not sufficiently described the instant methods because there is insufficient correlation between the functional characteristics required by the claimed methods of treating and the disclosed structures. The examiner’s discussion of individual elements of the claimed invention above, rather than to point to any individual component not described, is pointing to why, even where individual components may exists in the art, the Applicant’s disclosure is insufficient to identify a structure/function correlation encompassing all of the genus of the methods of treating because the individual structural limitations would not be sufficient to allow an artisan to envisage which variants of the claimed methods (e.g. which T cells comprising a CAR and an iCAR) would sufficiently treat cancer or inhibit neurotoxicity. The artisan could not envisage all of these methods because it would not have been predictable at the time of filing which of the millions of CAR-T cells comprising a CAR and iCAR pair largely defined by functional properties as claimed would effectively treat cancer or inhibit neurotoxicity.
Applicant further argues that the point of view and knowledge of those of ordinary skill in the art was sufficient at the time that Applicant did not need to include in the specification an extensive number of examples and that as such “the specification readily conveys to those skilled in the art the sufficient, relevant, and distinguishing characteristics of the specified domains that could be combined to created operative CAR and iCAR constructs” (Remarks 9/10/2025 p. 18-19). This is not persuasive, because, as described above, an artisan would recognize that these individual domains and the CAR and iCAR pairs built from them do not represent a predictable, structurally related group of proteins that all possess a combination of characteristics that would result in the method of treating cancer or inhibiting neurotoxicity as claimed. Even though they are perhaps the most well-described CAR-T cells in the art not all anti-CD19 CAR-T cells possess the same degrees properties, and failures of methods of treating CD19+ cancers with CD19 CAR-T cells have been described (Li, Xiaoqing, and Weihong Chen. "Mechanisms of failure of chimeric antigen receptor T-cell therapy." Current Opinion in Hematology 26.6 (2019): 427-433). For example, the ZUMA-1 trial and JULIET trials showed 83% and 52% ORR rates respectively (Li et. al. Table 1). It is therefore not evident from the instant specification how an artisan would go about identifying the anti-CD146 iCAR that would preserve the method of treating cancer in each case. An artisan would understand that each iCAR comprising an inhibitory signaling domain of the PD-1, wherein the inhibitor signaling domain provides and inhibitory signal to the modified T cell upon engagement of the iCAR with its target to inhibit or suppress the cytotoxic activity of the modified T cell would be expected to behave differently in the context of each CAR. Unlike CD-19 CARs, there are no species of anti-CD146 iCARs described at the time of filing. The instant methods as claimed, for example, encompass an iCAR that constitutively dampens the cytotoxic activity of the T cell. There is no evidence of record that an artisan would be able to determine which of the anti-CD146 iCARs functions constitutively as opposed to only “upon engagement”; thus, this would need to be determined experimentally. How can the instant method be described when applicant only prophetically mentions the required CARs by individual domains and the function of the pieces, but the pieces cannot be predictably combined to perform the requisite functions?
Claim Rejections - 35 USC § 112(a)- Enablement- Maintained, modifications necessitated by amendment
Claims 34, 36, 46, and 47 are rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
M.P.E.P. § 2164.01 states:
The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors, which have been outlined in the Federal Circuit decision of In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), include, but are not limited to, the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed. See also Ex parte Forman, 230 USPQ 546 (BPAI 1986).
The amount of guidance, direction, and exemplification disclosed in the specification, as filed, would not have been sufficient to have enabled the skilled artisan to make and/or use the claimed invention at the time the application was filed without undue and/or unreasonable experimentation.
The reasons it is submitted that the specification would not reasonably enable the skilled artisan to use the claimed invention without undue and/or unreasonable experimentation are essentially the same as the reasons the claims have been rejected as failing to satisfy the written description requirement. Any product or any process that has not been adequately described with the requisite clarity and particularity to permit the skilled artisan to make or use that product or process cannot be made or used without undue and/or unreasonable experimentation. This was as of the filing date sought by Applicant the state of the art and it remains so today.
“[Although] written description and enablement often rise and fall together, requiring a written description of the invention plays a vital role in curtailing claims that do not require undue experimentation to make and use, and thus satisfy enablement, but that have not been invented, and thus cannot be described” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1352, 94 U.S.P.Q.2d 1161, 1173 (Fed. Cir. 2010). It follows then that if a product or a method is not described with any of the requisite clarity and particularity to convey its actual invention (i.e., its conception and reduction to practice), it cannot be practiced without undue experimentation.
Breadth of the claimed invention; Guidance/working Examples
As described in the written description above, the claims are directed towards a method of treating cancer or inhibiting neurotoxicity comprising administering to a human subject in need thereof any T cell comprising:
A CAR comprising: i) any antigen binding domain specific for CD19 epitope comprising SEQ ID NO: 30, ii) a CD8 transmembrane domain, iii) any intracellular signaling domain comprising a CD3-zeta signaling domain
An iCAR comprising: i) any antigen binding domain specific for CD146, ii) a PD-1 transmembrane domain, and iii) any intracellular signaling domain comprising an inhibitory signaling domain of PD-1 wherein the inhibitory signaling domain provides an inhibitory signal to the modified T cell upon engagement of the iCAR with its target to inhibit or suppress any activity of the modified T cell
As such it merely represents an invitation to others to finish the inventive process and cannot be regarded as sufficiently enabling. See Rasmussen v. SmithKline Beecham Corp., 413 F.3d 1318, 1325 (Fed. Cir. 2005) (“If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to ‘inventions’ consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the ‘inventor’ would be rewarded the spoils instead of the party who demonstrated that the method actually worked.”). There are no working examples of the specific structures of an anti-CD19 CAR or an anti-CD146 iCAR, and especially not a specific pair each comprising a defined peptide structure; there are no examples of a T cell comprising the CAR/iCAR pair and what “providing an inhibitory signal […] to inhibit or suppress the activity of the modified T cell” or the degree or structures required to 1) provide the activating signal to treat cancer while simultaneously 2) provide the inhibitory signal to suppress the activity where required.
Applicant is reminded that reasonable correlation must exist between the scope of the claims and scope of enablement set forth.
State of the Art/Predictability
As described in the written description rejection above, while an artisan may be able to choose a piece fitting each part of the limitations of the T cell and method, these would not be expected to be able to substitute predictably for one another. Federov specifically teaches that each CAR/iCAR pair will need to be optimized for several factors for clinical use (Discussion, para 6). This lack of predictability for the T cell functioning with a CAR/iCAR pair remains true as shown in Hamburger et. al., which demonstrates different inhibitory and excitatory properties of T cells comprising CAR/iCAR based on target antigen density and by Partin et. al. which demonstrates that epitope and structural properties of the CAR/iCAR interaction matter for the T cell inhibitory signal as discussed in the written description rejection above.
Summary
The instant specification and the art at the time of filing does not enable a person of skill in the art to make and use the genus of methods and T cells comprising anti-CD19/anti-CD146 CAR/iCAR pairs as claimed. There is little specific guidance or examples on the required structure of the T cells and CAR/iCAR pairs and therefore it would take an undue level of experimentation to practice the methods as claimed for treating cancer or inhibiting neurotoxicity. Dependent claims are rejected for not resolving the enablement issue as described.
Response to Arguments
Applicant’s arguments filed 10 September 2025 have been fully considered but are not persuasive.
Applicant argues that “any assertion that the specification would not reasonably enable the skilled artisan to use the claimed invention for essentially the same as the reasons as failing to satisfy the written description requirement is misplaced”. This is not persuasive because the enablement rejection is separately stated. MPEP 2164.01(a) describes the undue experimentation factors that should be considered. The enablement rejection states, "Any product or any process that has not been adequately described with the requisite clarity and particularity to permit the skilled artisan to make or use that product or process cannot be made or used without undue and/or unreasonable experimentation." The enablement rejection includes explanation of the factors concerning (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. Thus, the rejection is valid.
Applicant argues that “the claimed invention has been described in at least Fig. 4A-4H, pages 67, lines 30-31, page 68 lines 1-2, 13-20, and Examples 3 and 4. Fig. 4B depicts a representative of the CAR constructs used in the study and Fig. 4A shows the CD19 sequences for both mouse and human that were used”. This is not persuasive because these examples do not fall within the scope of the claims because the CAR-T cells described in Examples 3 and 4 do not fall within the scope of the instant methods of treatment because they do not comprise the claimed anti-CD146 iCAR. Applicant further argues that “the art is replete with references to the various CAR domains in the field of chimeric receptors, evidencing that these terms/domains were known, commonly used, and readily understood by a person of ordinary skill in the art; and a preliminary review of U.S. patent literature reveals hundreds of granted U.S. patents spanning at least a decade before January 15, 2020 through to the present that contain claims reciting identical or nearly identical terminology” (Remarks 9/10/2025 p. 21-22). This is not persuasive because each patent is assessed individually for patentability based on the instantly claimed invention and the instant specification. It is not sufficient to show that specific gene terms or CAR domains were well known in the art at the time of invention to determine that applicant was enabled. Additionally, there is currently no evidence of record that, for example, and anti-CD146 CARs of any kind were described in the art. In addition to the Discussion of Fedorov et. al. as cited, the more recent publication Han, Xiao, et al. "Multi-antigen-targeted chimeric antigen receptor T cells for cancer therapy." Journal of hematology & oncology 12.1 (2019): 128 states: “Several crucial factors profoundly influence the function of iCAR-T cells, and special attention will be required in the future clinical application phase, including toward the affinity and expression level of iCARs, appropriate target antigen selection and the optimization of the CAR/iCAR ratio [51] (Fig. 2d)” (p. 8, left column). MPEP 2164.01 describes the Wands factors that should be considered in order to determine compliance with the enablement requirement. As described above, the methods of treatment and methods of inhibiting neurotoxicity comprise a large breadth of methods comprising administering a large genus of T cells comprising a CAR and an iCAR. The examiner would like to note in particular that the claims of inhibiting neurotoxicity still encompass a method wherein a traditional anti-CD19 CAR-T cell is first administered, inducing neurotoxicity, followed by administration of the T cells comprising the CD19 CAR/CD146 iCAR. Based on the instant specification, there are no embodiments where the instant iCAR inhibition would be predicted to function extracellularly or in trans with traditional anti-CD19 CAR-T cells. The state of the art was such that methods of treating cancer with anti-CD19 CARs were known, but methods comprising iCARs were much less well described, as described in the written description rejection above. There are no working examples disclosed in the specification. It would have been unpredictable, based on the state of the art and the specification, which of the claimed methods would be functional to treat cancer or inhibit neurotoxicity as described. Thus, it would have taken undue experimentation to determine to perform the method of treating cancer or the method of inhibiting neurotoxicity as described because it was unpredictable what pieces of the CAR and iCAR individually and jointly as a pair would operate together to perform the instantly claimed methods; each embodiment would have to be tested individually, which would encompass millions of embodiments.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Prior art made of record and not relied upon is considered pertinent to Applicant's disclosure (all references are of record):
Zhao et al. (Mol. Ther. Oncolytics. 2020 Jun 24; 18: 272-81) teaches a method of treating B cell acute lymphoblastic leukemia (B-ALL) in human subjects, said method comprising administering to the subject an effective amount of a modified autologous T cell comprising a chimeric antigen receptor (CAR) comprising an extracellular antigen binding domain comprising an scFv derived from the human CD19-specific antibody FMC63, a hinge and CD8a transmembrane domain, and an intracellular signaling domain comprising a human CD3z activation domain; see entire document (e.g., the abstract; and page 277). Zhao et al. teaches that the T cells expressing a CAR comprising a human 4-1BB-derived intracellular costimulatory domain were more effectively used to treat the disease than T cells expressing a CAR comprising a human CD28-derived intracellular costimulatory domain (see, e.g., the abstract). Furthermore, Zhao et al. reports the finding that when the former cells were used to treat the disease, the incidence of severe immune effector cell-associated neurotoxicity syndrome (ICANS) in the subjects (patients) was diminished substantially (see, e.g., page 275; and Figure 6F). In fact, as Zhao et al. discloses severe ICANS occurred in three patients after infusion of CAR-T cells comprising the human CD28-derived intracellular costimulatory domain, but that this unwanted side-effect did not occur in any of the patients that received infusions of CAR-T cells comprising the human 4-1BB-derived intracellular costimulatory domain (page 275).
Gust et al. (Cancer Discov. 2017 Dec; 7 (12): 1404-19; author manuscript; pp. 1-28) teaches endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells as a consequence of the development of cytokine release syndrome (CRS); see entire document (e.g., the abstract). Gust et al. teaches patients suffering from severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability, which failed to prevent the introduction of high concentrations of systemic cytokines, including IFN-g into CSF, which caused brain vascular pericyte stress and their secretion of endothelium-activating cytokines (see, e.g., the abstract); and finally, with regard to the cause of the neurotoxicity associated with CD19 CAR-T cell therapy, Gust et al. teaches that a direct effect of targeting CD19 cannot be excluded (see, e.g., the abstract).
Parker et al. (Cell. 2020 Oct 1; 183 (1): 126-42; electronically published September 21, 2020) teaches brain mural cells (including, in particular, pericytes) express CD19, possibly accounting for the evident off-tumor target neurotoxicity associated with CD19 CAR-T cell therapy; see entire document (e.g., the abstract).
Fedorov et al. (Sci. Transl. Med. 2013 Dec 11; 5 (215): 215ra172; pp. 1-12) teaches PD-1-based inhibitory chimeric antigen receptors (iCARs) for use in diverting adverse off-tumor target immunotherapy responses; see entire document (e.g., the abstract). Furthermore, Fedorov et al. teaches iCARs can function as dynamic, self-regulating safety switches to prevent the unwanted consequences of inadequate CAR T cell specificity by temporarily restricting cytotoxicity when both a therapeutic CAR and an iCAR, which are co-expressed by the same T cell, are simultaneously engaged (see, e.g., the abstract); and in addition, Fedorov et al. teaches the iCAR approach is antigen-specific and thus requires the ability to identify tissue-specific target antigens that are absent or down-regulated on the tumor, but expressed by the off-target tissues (e.g., HLA-DR); see, e.g., the abstract. Fedorov additionally teaches that the iCAR has “a surface antigen recognition domain combined with a powerful acute inhibitory signaling domain to limit T cell responsiveness despite concurrent engagement of an activating receptor” (Introduction, para 4) and “iCAR-positive T cells were significantly inhibited in their ability to kill iPS-fib-PSMA+ cells” (iCARs limit TCR responses in an antigen-restricted manner, para 2, Fig. 2C).
Chen et al. (Proc. Natl. Acad. Sci. USA. 2017 Sep 5; 114 (36): E7622-E7631) teaches CD146 is expressed by pericytes in the human brain, where it functions to coordinate the interactions of pericytes with endothelial cells at the endothelial junction to regulate the development and permeability of the blood-brain barrier, as well as vessel integrity; see entire document (e.g., the abstract; and page E7624).
U.S. Patent Application Publication No. 20220127373-A1 (Lim et al.) teaches an iCAR comprising a transmembrane domain, which is the transmembrane domain of human PD-1; see entire document (e.g., paragraph [0111]).
Tao et al. (Cancers (Basel). 2020 Sep 13; 12 (9): 2612; pp. 1-17) teaches an iCAR comprising the extracellular domain of KIR2DL2 and the intracellular domain of PD-1, which functions to discriminate between normal cells (HLA-C1+) and