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 .
This office action is in response to a claim set filed 3/10/2025.
Claims 1, 3, 5, 7, 8, 11, 17-21, 45, 46, 50, 52, 54-56, 58 and 59 are pending. Claim 6 is listed as cancelled but accompanied by text. This is improper based on CFR 1.121 which requires that cancelled claims not be accompanied by text.
This application is a 371 filing of PCT/US2023/068456 filed 6/14/2023 which claims priority to U.S. provisional application 63/351,906 filed 6/14/2022 and U.S. provisional application 63/416,026 filed 10/14/2022.
Information Disclosure Statement
An IDS filed 3/6/2024 has been identified and the documents considered. The signed and initialed PTO Form 1449 has been mailed with this action. Initials indicate that the document has been considered even if the reference is lined through. In the case that only an English abstract was identified, this is indicated.
Claim Objections
Claim 5 is objected to because of the following informalities: Although claims are allowed abbreviations, if an abbreviation is not spelled out upon first use in a claim, MPEP §2429 states that Applicant only use abbreviations that are specifically defined in "WIPO Standard ST.25 (1998)" or that are well known and would be clear to someone who had not read the invention description. In claim 18, T-CAR should be spelled out as to the meaning of “T”. Alternatively, once the abbreviated term has been established the abbreviation should be used. In claim 45, this is true of CAR and PSC. As well as claim 50.
Claim 21 refers to nucleotide sequences wherein the proper format should be –is encoded by the nucleotide sequence of--. SEQ ID NO:s are place holders and not actual sequences `and hence the nucleotide sequence provides for the sequence being referenced.
In claim 59, the article “the” should be provided prior to “second”. These are independent limitations and not compound nouns and each require their own article. This would be true of claim 58 but this occurrence of second therapies appears to be in error as set forth below.
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.
Claims 5, 11, 56 and 58 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims referring to Markush groups of claims are confusing and unclear. Claim 5 recites that the nanoparticles comprise “one or more” of a group that ends with “and/or”. It should simply be “and” as it makes unclear if the list prior to “and/or” is one choice and “fullerene” the other. Claim 8 is entirely confusing as to the choice of drug. The use of multiple “or” linkages in the claims makes unclear what the grouping is. It is unclear if there are three choices or if the list is one single choice. Claim 11 similarly by reciting “and/or” and “or” in the same grouping breaks up the groups in a complicated manner. Claim 56 also does not clearly indicate the groupings.
Claim 58 recites the limitation "second therapies" in claim 50. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 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 50, 52, 54-56, 58 and 59 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method of treating glioblastoma by administering locally to the brain autologous neutrophils encoding a CAR comprising an anti-GBM chlorotoxin (CLTX) and a T-specificCD3ζ, does not reasonably provide enablement for any other embodiment. 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 test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims are drawn to a method of treating cancer with CAR neutrophil cells.
2) Scope of the invention. The scope of the invention is extremely broad in that the cancer is any as is the corresponding target antigen of the CAR. As well, the source of the neutrophils is not specified.
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3) Number of working examples and guidance. The specification teaches construction of 4 CAR structures each comprising a single peptide from GM-CSFR, an anti-GBM chlorotoxin (CLTX) signal peptide, IgG4 linker, a transmembrane domain and intracellular domain from CD3z and/or CD32a-ITAM. These were constructed on vectors designed to integrate into the Avs1 donor site of PSC. “Since primary neutrophils are short-lived and resistant to genome editing, hPSCs were engineered with these CARs to achieve stable and universal immune receptor expression on differentiated neutrophils by knocking CAR constructs into the AAVSI safe harbor locus via CRISPR/Cas9-mediated homology-directed repair” [[0199]]. Thereafter the PSC were differentiated into neutrophils. These cells were observed in vitro to not kill healthy cells but those CAR with CD3z showed anti-tumor activity even under TME mimicking conditions (example 1 and 2).
CAR neutrophils were loaded with R-SiO2-TPZ nanoparticles CAR-neutrophils@ R-SiO2-TPZ and demonstrated cytolytic activity in vitro in cell culture, with biomimetic GBM models and tumor spheroids. CAR-neutrophils@ R-SiO2-TPZ crossed the blood brain barrier and migrated to the tumor cells and in the spheroid migrated to the center with uniform distribution.” Taken together, the combinatory CAR neutrophils and nanodrugs displayed excellent anti-tumor activities in biomimetic TME-mimicking conditions in vitro, highlighting the therapeutic potential of combinatory neutrophil-based chemoimmunotherapy”. In mice glioblastoma models, the CAR-neutrophils@ R-SiO2-TPZ were localized in the brain following intravenous administration.
Results were shown for an Anti-PSMA J591 CAR neutrophil loaded with SiO2-TPZ. But, it is not clear what tumor model or system is targeted. Applicants disclosure is limited to demonstration of proof of principle using CAR-neutrophils@ R-SiO2-TPZ wherein the CAR comprises CLTX, chlorotoxin directed against GBM.
4) State of the art. The claims are directed at treating any cancer thus embracing a broad group of cancers and correlative CAR neutrophil cells as the CAR is designed with binding domains that direct the immune cell to the tumor Mishra et al (Vaccines, 2023, pages 1-23, see Figure 1). Considering any cancer, at the time of filing there was a huge gap in the ability to treat non-hematological conditions with CAR cells. Mishra et al reviews these issues (Figure 3 and bridging ¶ pages 14-15).
However, all these CAR-T-cell products have shown adverse side effects, such as neurotoxicity and CRS, in different clinical trials for MM (KarMMAa, CARTITUDE 1, LEGEND 2). Many structural limitations and their associated toxicities remain to be addressed (Figure 3)
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Figure 3. Limitations of CAR-T-cell therapy: (A) On-target/off-tumor attacking of the normal cell by CAR T cell if the same target antigen is present on the tumor cell. (B) The immunosuppressive microenvironment of the tumor cell consists of chemokines, and growth factors that lead to the infiltration of immune cells in the tumor. (C) CAR-T-cell toxicities: the pathogeneses of immune effector cell-associated neurotoxicity syndrome and cytokine release syndrome occur after the interaction of the tumor cell with the target antigen on the tumor cell.
Applicants experimental work shows proof of principle for using CLTX CAR to treat glioblastoma. For this disorder, tumor heterogeneity and adaptation to treatment has been a huge obstacle glioblastoma (Wang et al, Sci. Transl. Med.2020, pages 1-14, see page 1, col 1-2). Wang demonstrates improvement on these issues by use of the claimed CLTX peptide.
5) Unpredictability of the art. As shown above, the obstacles to CAR cell therapy are well documented. The instant invention is complicated by not only this lack of predictability but also that the claims are drawn to treating any cancer with any CAR therapy. To date, in fact, and as set forth above, CAR therapy has shown little success with non-hematological cancers. CAR therapy is designed to comprise components designed for specific target therapy. Applicants only disclosure highlights this criticality. Wherein even closely related CAR molecules have differing effects. CAR#$ does not perform any better than PB neutrophils (see Figure 2D).
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Even considering the limited successes, there is little universality to CAR cell therapy (see Lei et al, Molecular Cancer, 2026, pages 1-28, see page 2, col 1). Applicants have shown successful targeting in vitro and in mice models for glioblastoma with CAR comprising CTLX with CD3z intracellular signaling domains.
It is noted that mice models are useful as proof of principle but do not recapitulate the complexities of human delivery systems (Wen, Ann Transl Med 2019, pages 1-18, bridging ¶, col 1-2, page 2).
Due to their lack of a host immune system, CAR-Ts are incapable of simulating the cascade reaction caused by CRS in these immunodeficient mice as occurs in patients, and interactions among CAR-T cells and other immune cells/tissue are also unable to be detected in these models, in addition to the on-target, off-tumor effects. However, what cannot be ignored is that they are currently the optimum preclinical research system for predicting neurotoxicity, graft versus host disease (GvHD), effects of CAR-T to local tissues, and the macrophage activation syndrome (MAS) (13). Along with the choice of animal models, we are facing another challenge in shaping feasible toxicological study schemes to capture the characteristics of CAR-T products.
Begley et al provide direction on CAR cell therapy for human therapy and this provides that the state of the art requires local administration. The obstacles even with improved targeting as shown by applicants CAR in mice is not enough to overcome the homing issues found in humans (see page 2458, col 2). As well, the state of the art while desiring allogeneic cells for therapy must rely on autologous cells (see page 2458, col 2).
6) Undue experimentation. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention. Furthermore, the relationship of enablement with the requirement for written description is acknowledged by the MPEP. To this end, the court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eli Lilly& Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description of a nucleic acid requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the nucleic acid itself. It is not sufficient to define DNA solely by its principal biological property, because disclosure of no more than that, as in the instant case, is simply a wish to know the identity of any DNA with that biological property. Naming a type of material generically known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.
Applicants have claimed a large genus of CAR sequences any sources of neutrophils to trat glioblastoma. However, their description is of a limited set of sequences that mediate this function. Furthermore, there is an art acknowledged lack of correlation of any CAR trading any cancer. Consequently, the prior art (and post-filing art) when combined with the lack of any disclosed direct experimental test of Applicant's hypothesis, shows that one of skill in the art at the time the invention was made would have had no basis to reasonably predict or conclude the claimed sequences could be identified given the lack of details necessary to identify those meeting the necessary functions. Though not controlling, the lack of working examples, is, nevertheless, a factor to be considered in a case involving both physiological activity and an undeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, he runs the risk that unless one with ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilovsky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
Claim Rejections - 35 USC § 112, first paragraph
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.
Claims 19-21 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.
Claim 19 recites that the neutrophils are of the N1 phenotype. However, the neutrophils are differentiated from PSC and it is not clearly described how one would differentiate the neutrophils to a specific phenotype. The disclosure simply teaches that there are two phenotypes anti-tumor N1 and pro-tumor N2 phenotypes of TANs have been found within the hypoxic TME. But, there is no indication of how to differentiate towards one and not the other.
Claim 20 recites that the neutrophils exhibit anti-glioblastoma activity in a hypoxic tumor microenvironment. This means the claims while dependent on a product recite a structure by function without clear indication as to the structure that accompanies this function.
Claim 21 recites that the CAR ius encoded by SEQ IDNO:2,, 3, 4 or a functional variant. However, the only sequences provided for are SEQ IDNO:2, 3, 4 and as to functional variants, the disclosure does not provide the relevant identifying structural or functional characteristics that must be used to identify the variants thereof. The written description requirement for genus claims may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with known or disclosed correlations between function and structure, or by a combination of such characteristics sufficient to show that the applicant was in possession of the claimed genus.
To this end, the MPEP provides such guidance (emphasis added). If the application as filed does not disclose the complete structure (or acts of a process) of the claimed invention as a whole, determine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Compare Fonar, 107 F.3d at 1549, 41 USPQ2d at 1805 (disclosure of software function adequate in that art).
Claim Rejections - 35 USC § 103
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 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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3, 7, 18 , 45, 46, 50, 52, 54, 56 and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Matlung (U.S. 20240366762) as evidenced by Roberts et al (J. Immunol. 1998, 161, 375-384) in view of Xue et al (Nature Nanotechnology, 2017, pages 692-702).
Matlung teaches treatment of disorders such as glioblastoma with CAR neutrophils (see ¶0070 and 0101). That the neutrophils are differentiated from PSC is a product by process claim and absent evidence of properties related to the process, the neutrophil is the same as that taught in Sanquin. Furthermore, as the claim is a product claim it must be evaluated as to the product.
Xue et al teach improvement of cancer therapy by use of neutrophils carrying paclitaxel in nanoparticles (see abstract and figure 1).
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to incorporate nanoparticles of Xue and CAR of Matlung to make a cell with improved specificity and cytotoxicity (see Roberts, abstract). Such a modification would have resulted in a composition and method encompassed by claims 1, 3, 7, 18 , 45, 46, 50, 52, 54, 56 and 59. As noted above: 1) both references are drawn to modifications of neutrophils to treat glioblastoma 2) Matlung teaches that neutrophil use would improve CAR therapy, [0069]], “Innate cells, including neutrophils and macrophages, are essential effectors of the immune system. Harnessing these innate cells against tumor cells is of longstanding interest, especially in the case of solid tumors, where existing T cell therapies have limited success” 3) Xue teaches that neutrophils penetrate inflamed brain tumors and can carry drugs to the tumor. Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the combined composition would allow improved treatment.
Roberts provides description of the claimed embodiments. As recited in claim 3, the neutrophils are human (see Roberts et al, page 382, col 2).
Paclitaxel is a chemotherapeutic drug as recited in claim 7.
Matlung teaches pharmaceutical compositions comprised therein (see ¶0026).
Matlung teaches use of HER2, EGFR and other glioma targeting antigen binding domains (see ¶0138) as recited in claim 18 directed to. It appears that the cells are simply a product by process and hence meet claim 50 and hence claim 52.
Xue teaches intravenous administration in mice but also intracranial implantation is applied (see Figure 1 and page 695, col 2) as claimed in claim 54. As claimed in claim 55, 56 and 59, Xue et al teach administration of taxol sequentially with CAR (page 702, col 2).
Claims 5, 8 11, 17, 20, 21 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Matlung (U.S. 20240366762) as evidenced by Roberts et al (J. Immunol. 1998, 161, 375-384) in view of Xue et al (Nature Nanotechnology, 2017, pages 692-702) as applied to claims 1, 3, 7, 18 , 45, 46, 50, 52, 54, 56 and 59 above, and further in view of Karathanasis et al (U.S. 20190111133) and Ding and Lamb (U.S. 20220259768).
Karathanasis et al as recited in claim 5 and 8 teach that linkage of mesoporous silica with temozolomide is therapeutic for glioblastoma including hypoxic conditions in glioblastoma . Imaging agents are also used wherein the process is imaged (see figure 5).
The constructs of claims 11 and 17 were shown in the art as demonstrated by Ding et al, see figure 1 for structure and components provided for in ¶0003, 0040, 0042, 0152 which provides for every recited component for treatment with CAR directed to glioblastoma. These appear to be functional variants of the sequences in SEQ ID NO:2 given the structurally corresponding components.
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to modify the CAR neutrophil cells comprising drug-nanoparticles of Xue in view Matlung to with the related variables provided for by Karathanasis and Ding et al as these teachings provide details related to the compositions and uses taught by Xue and Sanquin. They are obvious variants of the teachings and would have been obvious to use for improved and detailed methods and compositions.
Conclusion
Claim 19 recites components that are difficult to search given the lack of description. Hence, it is not clear they are free of the art.
Additional references consulted,
Chang et al, Cell Rep, Engineering chimeric antigen receptor neutrophils from human pluripotent stem cells for targeted cancer immunotherapy, 2022, pages 1-37
Chang et al, CAR-neutrophil mediated delivery of tumor microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy, Nature Communications, 2023, pages 1-17
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/MARIA MARVICH/Primary Examiner, Art Unit 1634
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