DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response and amendments received August 17, 2026 are acknowledged.
Claims 9, 13, 15, 16, 18-20, 26, and 29-42 have been canceled.
Claims 7 and 8 have been amended.
Claims 1-8, 10-12, 14, 17, 21-25, 27, 28, 43, and 44 are pending in the instant application.
Applicant’s election of the antigen species bound by the “cellular immunotherapeutic” to be “dysfunctional (nf)P2X7 receptor” in the reply filed on August 17, 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 1-8, 10-12, 14, 17, 21-25, 27, 28, 43, and 44 are under examination in this office action.
Information Disclosure Statement
The IDS forms received 5/1/24, 9/6/2024, 10/21/2025, 6/1/2026, and 8/17/2026 are acknowledged and the references cites therein have bene considered.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-8, 10-12, 14, 17, 21-25, 27, 28, 43, and 44 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 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.
Applicant has broadly claimed methods wherein a subject previously administered a cellular immunotherapeutic, such as a CAR T cell, is administered “a molecule for binding the cellular immunotherapeutic, wherein the molecule comprises or consist of an epitope of the target antigen” thereby competing with the target antigen (such as that expressed on the tumor cells) for binding to the “cellular immunotherapeutic” such that the activity of the “cellular immunotherapeutic” is inhibited. In addition to simply inhibiting the binding of the “cellular immunotherapeutic” to its target ligand (i.e. claim 1), such methods are further recited as achieving the results of “reducing the risk of an aberrant inflammatory response” (claim 4), “treating an aberrant inflammatory response” (claim 5), and increasing persistence of cellular immunotherapeutics (claim 8). The majority of claims recite no specific structure for either the “cellular immunotherapeutic” or the administered “molecule for binding the cellular immunotherapeutic” while claims 27 and 28 specify the target bound by the cellular immunotherapeutic. To support such breadth, the working examples disclose that 4 soluble peptides comprising the E200 epitope of the P2X7 receptor were able decrease killing activity of cells expressing a CAR recognizing dysfunctional P2X7 in a titratable manner. Data demonstrating inhibition of CARs specific for other antigens, either alternate epitopes of (nf)P2X7 or structurally unrelated molecules such as those presently recited in claim 27, by soluble cognate antigens has not been provided.
Applicant’s claimed inventions appear to be predicated on the phenomena of competitive inhibition, a phenomena long known to be strongly impacted by reagent concentrations as readily demonstrated by applicant’s ability to titrate (nf)P2X7CAR killing activity in a soluble peptide concentration dependent manner (see most explicitly Figure 4). No discussion or guidance concerning suitable concentrations for therapeutic efficacy, such as needing to be X% above the local tumor microenvironment concentration of the target antigen, appear to be disclosed in the instant specification. What does appear to be assumed is that the P2X7 titration experimental result is applicable to all tumor antigens that are targeted by a “cellular immunotherapeutic” such as a CAR. However, such an assumption is not reasonable.
For example, Lanitis et al. were concerned that soluble mesothelin shed from tumors would inhibit the activity of anti-mesothelin CAR T cells and found that it did not, even when present at levels 5 times higher than seen in human patients (see entire document, particularly the paragraph bridging pages 637-638 and Figure 5, and note that the CAR was fully capable of binding soluble antigen (see Figure 5C in particular)). Similar results have been observed for other soluble antigens shed by tumors including Lewis Y (Westwood et al., see entire document), CEA (Nolan et al., see entire document) and CD30 (Hombach et al., see entire document). Such results are unsurprising given that Chang et al. teach that ligation of a CAR by a monomeric soluble ligand fails to result in activation of the CAR expressing cell while oligomeric ligand structures do activate the same CAR expressing cell, and that soluble ligands comprising multiple binding sites are capable of crosslinking, and thus activating, CARs (see entire document, particularly Figures 1, 4 and 6). Thus it appears that the precise molecular structure of the soluble antigen molecule, including how many epitopes are present that can bind the “cellular immunotherapeutic” are important concerning questions of activation or inhibition of the “cellular immunotherapeutic”.
As discussed earlier, the instant claimed inventions appear to be predicated on the idea that administering an (presumably as it is not recited) excess of a molecule comprising the epitope to which a CAR (or other “cellular immunotherapeutic”) binds will essentially bind all of CARs leaving none available to interact with the original target of the administered CAR, such as the tumor antigen expressed on the surface of the cancer. However, in contrast to the data observed in the instant working examples concerning a P2X7CAR and its E200 peptide ligand epitope, Lantis et al. could not inhibit the activity of their anti-mesothelin CAR even when soluble mesothelin was present at a great excess. Thus, not all antigen/CAR interactions appears to be titratable by soluble ligand such that the activity of the CAR can be reduced or eliminated. Note that as per for example paragraph [0023] of the instant specification, the ability to “turn off” signaling through the CAR by flooding the system with excess ligand is the mechanism by which applicant believes “increasing cellular persistence” occurs and CAR cells thus treated get a “rest” that prevents their clonal exhaustion. It should be appreciated that the data of the instant working examples do not address the issue of clonal exhaustion/cellular persistence, but based upon data such as that disclosed above from Lanitis et al. and others using multiple soluble antigens, stopping activation of CAR cells by providing alternate ligand peptides is not generically possible. Further, based upon mechanistic considerations such as those disclosed by Chang et al., any “molecule for binding” must be monomeric for the binding epitope to have any chance of working as bi-and multivalent epitopes will simply mimic the structure found on the surface of a tumor cell which results in CAR crosslinking and cellular activation. Notably, the number of epitopes present in the administered “molecule for binding” never appears to be explicitly recited and the specification does not appear to discuss this design aspect and its importance to achieving the results explicitly recited in the claimed methods. Further, as discussed by Lindner et al., signaling through CARs is similar to, but distinct from, that of a naturally occurring TCR, and signaling events in CARs are likely to be distinct one from another based upon such things as ligand binding affinity, spare length, the numbers and identity of intracellular signaling domains and the choice of host cell for the CAR, all of which influence what happens when the CAR binds its ligand (see entire document, particularly the conclusion section). Therefore, data obtained for one particular CAR-ligand interaction pair is reasonably expected to not be directly applicable to other CAR/ligand systems.
One of intended results recited for the instant claimed methods is to treat cytokine release syndrome (a subset of “aberrant inflammatory responses”) by administering a “molecule for binding” which disrupts the binding interaction between the CAR/”cellular immunotherapeutic” and the tumor cell such that the CAR no longer signals leading to cessation of cytokine secretion. Cytokine release syndrome is a well known side effect of CAR therapy, with the severity of the problem typically correlated with the amount of CAR infused as well as the level of tumor burden prior to therapy (see for example the entirety of Frey et al., particularly Table 2). In severe cases, a quick acting therapy is necessary and artisans presently typically administer tocilizumab, an antagonist antibody that binds the IL-6 receptor, to rapidly reduce cytokine toxicity (ibid, and Figure 1). While clinical data exists demonstrating a rapid improvement in clinical symptoms following administration of antibodies that neutralized IL-6R (as well as IL-6 itself) data concerning speed and efficacy of the instant claimed methods in similarly treating CRS and its physiological symptoms are not known, it does not appear reasonable that artisans would practice the instant claimed CRS treatment methods in lieu of administering tocilizumab in the absence of such data. Further, given the potential life threatening consequences of a cytokine storm, it is not reasonable for artisans to experiment on their patients to determine if the claimed inventions do or do not work as applicant hopes and asserts that they do.
Therefore, based upon the breadth of the claimed inventions, the teachings of the art, and the limited guidance and direction of the instant specification, artisans would be unable to reasonably practice the full extent of what has been presently claimed without first conducting additional unpredictable basic science research and experimentation.
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 27 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 27 initially appears to recite standard Markush language (i.e. “antigen selected from the group consisting of”) concerning the tumor antigen bound by the “cellular immunotherapeutic”. However4, within the list itself the term “and especially EGFR, mesothelin …” appears. All members of a Markush are assumed to be of equal weight and selected at random, and thus what does “especially” mean with regard to the claimed invention? Does one of the “especially” antigen need to be present in order to satisfy the claim, and if so what purpose do the preceding antigens play? If any recited antigen is present, is “especially” essentially equivalent to “for example” and note that as set forth in MPEP § 2173.05(d) examples are not limiting and should not be recited in the claims. Thus the metes and bounds of the claim are not clear due to the recitation of “especially”. Deletion of “especially” from the claimed invention is the most straightforward way to obviate this rejection.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 6-8, 10, 11, 14, 17, 24, 25, 43, and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sahin et al. (WO 2015/113576, of record).
Sahin et al. disclose peptide mimotopes of claudin 18.2, a receptor overexpressed in many cancerous cells, that such mimotopes bind anti-claudin 18.2 CARs, and that such mimotopes can be administered to patients previously exposed to claudin 18.2 binding agents, such as CAR T cell as part of cancer treatment, to antagonize binding between claudin 18.2 and the claudin18.2 binding agents (see entire document, particularly the abstract, claims (in particular claims 39-44), and pages 1, 4, 15, 16, 24, 29, 32, 43, and 44). Chimeric antigen receptors are explicitly disclosed as being “binding agents to claudin 18.2” (see particularly pages 32, 43, and 44) and a CAR is very clearly a “cellular immunotherapeutic”. Given that the mimotopes are disclosed as being antagonist with regard to the “claudin 18.2 binding agent” (i.e. the CAR/”cellular immunotherapeutic”) they necessarily disrupt the interaction between the “claudin18.2 binding agent” and claudin 18.2 (i.e. the “target antigen”) and thus inhibit the activity of the cellular immunotherapeutic. Note such mimotopes are not disclosed as irreversibly binding to “claudin 18.2 binding agents” and thus the binding is reversable as any other ligand-receptor interaction which is necessarily true given that antigen recognition by a CAR recapitulates the interaction between the antigen binding domain of an antibody and its cognate ligand. Such mimotopes are disclosed as being joined to heterologous moieties such as in fusion proteins and to PEG to increase circulating half-life (see particularly claims 17-19 and pages 24 and 60). Conjugation to cytotoxic agents is also disclosed (see for example page 46).
It is noted that the methods of Sahin et al. do not disclose that their mimotopes “increase the persistence of a cellular immunotherapeutic” as is recited in the preamble of instant claim 8. However, as discussed above Sahin et al. disclose administering claudin 18.2 mimotopes to patients who previously received anti-claudin 18.2 CAR T cells for cancer therapy, and how such mimotopes antagonize the binding between the CAR and claudin 18.2. Given that the same active process steps are taught in the methods of Sahin et al. the intended result as precited in the claim preamble of instant claim 8 must occur as presently there is no difference when comparing the patients, reagents or process steps as recited in the instant claims to that which is disclosed in the prior art . Applicant is reminded that as per MPEP 2112, "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). While the instant claimed inventions are methods rather than products, the logic holds that if an artisan does the same things the same results must happen even if such outcomes were not previously observed or appreciated. Similarly, in instant claim 4, the subject does not have an aberrant inflammatory response at the time of administration, and thus since as discussed above the process steps are the same, benefits such as those recited in the preamble of “reducing the risk of an aberrant inflammatory response” necessarily must accrue to the patient as the same process steps have been performed.
Therefore, the prior art anticipates that which is presently claimed.
Claims 1, 4, 6, 7, 10, 11, 14, 17, 21, 24, 25, 27, 43, and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gill et al. (WO 2019/089798).
Gill et al. disclose anti-target CAR compositions which are disclosed as being administered to patients who previously were administered target CARs and are experiencing unwanted effects caused by the target CARs (see entire document, particularly the title, abstract, and claims). Notably such anti-CAR constructs are disclosed as comprising a cognate antigen molecule that bind the target CAR, for instance CD19 or a fragment thereof that binds to an anti-CD19 CAR (see for examples pages 2, 3, 10-12, and 68-70). Tumor antigens expressed by such anti-CARs include CD19, CD20, CD33, EGFR, and mesothelin (see particularly pages 3 and 4). Cells expressing such anti-CAR molecules are disclosed as encompassing CD8+ effector T cells and NK cells (see particularly page 12). Administration of anti-target CARs is disclosed for the treatment of disorders associated with the expression of a target CAR, such as but not limited to cancers wherein the tumor expresses the target CAR (see for example pages 17-24, 36, and 276-283).
It is noted that the methods of Gill et al. do not explicitly disclose that their methods of administering anti-target CAR reduce the risk of developing an aberrant inflammatory responses. However, as discussed above, the same process steps as recited in the instant claims are disclosed by Gill et al. Since the process steps are the same, any and all benefits of such a process, including those recited in claim preambles including “reducing the risk of an aberrant inflammatory response” necessarily must accrue to the patient as the same process steps have been performed. See also MPEP 2112.
Therefore the prior art anticipates that which is presently claimed.
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Michael Szperka whose telephone number is (571)272-2934. The examiner can normally be reached Monday-Friday 8:30-5:00.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
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