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 .
DETAILED ACTION
1. Applicant’s amendment filed 8/3/22 and Applicant’s amendment and response filed 7/6/26 are acknowledged and have been entered.
2. Applicant's election with traverse of Group III and the following species in Applicant’s amendment and response filed 7/6/26 is acknowledged:
-a soluble endogenous antigen of a TME;
-a first and second tagged polypeptide, one having an ABD specific for epitope A, the other having an ABD specific for epitope B of the soluble endogenous antigen in the subject and two additional tagged polypeptides having an ABD for epitope C and the other having an ABD for epitope D on the same second endogenous antigen of the subject, the two additional tagged polypeptides having the same tag as the first two polypeptides;
-NK-kB inducible promoter operably linked to a nucleic acid sequence encoding the CAR;
-the immune cell and the tagged polypeptide are contained in separate pharmaceutical compositions;
-the immune cell is a T cell and the effector function is cytokine secretion;
-the subject has cancer.
The basis for Applicant’s traversal is of record in the amendment and response filed 7/6/26 on pages 9-10. Applicant has presently amended the claims to recite that the one or more tagged polypeptides contain an ABD (antigen binding domain) specific for epitope A and an antigen binding site specific for epitope B, or multiple antigen binding sites specific for epitope E, wherein a soluble antigen that is endogenous to the subject comprises both epitope A and epitope B, or sufficient copies of epitope E such that binding of the tagged polypeptide(s) to the soluble antigen and binding of the immune cell to the tagged polypeptide(s) will result in activation of an effector function by the immune cell. Applicant argues that the reference cited in the prior office action of record does not teach or suggest using tagged polypeptides that contain ABDs that are specific for multiple epitopes or multiple copies of the same epitope so as to create an avidity effect.
However, Applicant’s arguments are not persuasive for the following reasons. Instant base claim 36 as presently amended recites “one or more tagged polypeptides, which together contain an antigen binding site specific for epitope A and an antigen binding site specific for epitope B, or multiple antigen binding sites specific for epitope E.” The art reference cited in the prior office action of record teaches tagged adaptor polypeptides (that are monovalent or bivalent, the latter being representative of multiple antigen binding sites specific for a particular epitope and that meets the present claim limitation) that are specific for a cell surface antigen of a tumor cell, such as for instance MSLN, EpCAM or EGFR, for use with an anti-tag CAR T cell. The evidentiary references teach that these said tumor associated antigens are also shed from tumor cells, i.e., they are soluble. For instance, evidentiary reference Ho et al. (of record) teaches that soluble mesothelin proteins (SMP) in cancer patient ascites or serum was identical to the ECD of a membrane-bound mesothelin and is the predominant protein present in the serum. Also, administration of a composition having more than one copy of a tagged adaptor polypeptide having an antigen binding site for a particular epitope taught by the art reference also meets the claim limitation (i.e., the one or more tagged polypeptides together contain multiple antigen binding sites specific for epitope E (epitope E being a generic placeholder for an epitope)). Applicant is arguing a non-recited limitation in arguing “avidity effect.” With regard to the newly recited limitation of ‘sufficient copies of an epitope such that binding of the tagged polypeptide(s) to the soluble antigen and binding of the immune cell to the tagged polypeptide(s) will result in activation of an effector function by the immune cell’, since the Patent Office does not have the facilities for examining and comparing the method of the instant invention to those of the prior art, the burden is on Applicant to show a distinction between the method of the instant invention and that of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977). Even if this were not so, the product of non-elected Group I is a combination of a CAR-T cell and one or more tagged polypeptides, the products used in the method of elected Group III are a CAR-T cell and one or more tagged polypeptides, whereas the product of non-elected Group II is a complex of an endogenous soluble antigen in a subject with one or more tagged polypeptides and a CAR-T cell; the product of Group II is a different product from that of the product of Group I. Thus, the claims are directed to multiple categories of inventions, two of which are different products, and the claims are therefore not considered to have unity of invention.
The requirement is still deemed proper and is therefore made FINAL.
Claims 19-21, 23, 25, 26, 28, 29, 31-33, 35, 36, 38 and 41 read on the elected species.
Accordingly, claims 22, 24, 27, 30, 37, 39, 40 and 42 (non-elected species of Group III) and claims 15-18 and 34 (non-elected Groups I and II) are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to non-elected inventions.
Claims 19-21, 23, 25, 26, 28, 29, 31-33, 35, 36, 38 and 41 are presently being examined as they read upon the elected species and the species enunciated below in the art rejection. Claims 35 and 36 are independent claims. The Examiner notes Applicant’s comments re: renumbering the claims in accordance with 37 CFR 1.126 upon allowance.
3. The disclosure is objected to because of the following informalities:
-The brief description of the drawings for Figures 3, 4, 5 and 7 lack descriptors for the parts a) and b) depicted in the said figures.
-The brief description of the drawings for Figure 6 lacks descriptors for parts a)-d) depicted in the said figures.
Appropriate correction is required.
4. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which Applicant may become aware in the specification.
5. 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.
6. Claims 19-21, 23, 25, 26, 28, 29, 31-33, 35, 36, 38 and 41 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. This is a written description rejection.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "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." See MPEP 2163 II.3.
Applicant has broadly claimed:
A method for treating a subject in need thereof with an immune cell that expresses a chimeric antigen receptor (CAR), the method comprising administering to the subject simultaneously or sequentially the following pharmaceutical agents:
Said immune cell, wherein the CAR expressed thereby contains:
an antigen binding domain (ABD) specific for a tag on one or more tagged polypeptides,
a transmembrane domain (TM),
an intracellular signaling domain; and
said one or more tagged polypeptides, which together contain an antigen binding site specific for epitope A and an antigen binding site specific for epitope B, or multiple antigen binding sites specific for epitope E;
wherein a soluble antigen that is endogenous to the subject comprises both epitope A and epitope B, or sufficient copies of epitope E such that binding of the tagged polypeptide(s) to the soluble antigen and binding of the immune cell to the tagged polypeptide(s) will result in activation of an effector function by the immune cell in the subject, thereby treating the subject (as is recited in instant base claim 36),
and including the limitations recited in the claims depending upon claim 36; or
A method of activating an effector function of an immune cell at the site of an endogenous soluble antigen in the subject, the method comprising contacting the soluble antigen with components (a) and (b) of the combination of claim 15 (as is recited in instant claim 35).
The specification does not disclose a representative number of species of one or more tagged polypeptides in the administered composition of the claimed method, which together contain an antigen binding site specific for epitope A and an antigen binding site specific for epitope B, or multiple antigen binding sites specific for epitope E on a soluble, endogenous antigen in a subject (i.e., species of tagged polypeptide that possess the functional property of binding specifically to an epitope, wherein the epitope is present on a soluble, endogenous antigen in vivo in a subject), and when bound to the soluble, endogenous antigen and to the adapter CAR immune cell, it possesses the functional property of activating an effector function in the adapter CAR immune cell), nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function.
The specification discloses that the terms “having specificity for”, “specifically binds” or “specific for” with respect to an antigen binding domain of an antibody, of a fragment thereof, or of a CAR refer to an antigen binding domain that recognizes and binds to a specific antigen, but does not substantially recognize or bind other molecules in a sample, or may be cross-species reactive (page 40 at lines 21-24). However, the specification does not disclose a limiting definition for “antigen binding site”, so the limitation may encompass antibody and non-antibody antigen binding sites, e.g., small molecules or other structures that are able to target an epitope of at least one antigen of interest. The specification discloses that the term “antigen” is intended to include substances that bind to or evoke the production of one or more antibodies, and may comprise but are not limited to proteins, peptides, polypeptides, oligopeptides, lipids, carbohydrates and combinations thereof (paragraph spanning pages 40-41). The specification discloses that the term “soluble antigen” as used herein refers to an antigen that is not immobilized on surfaces, i.e., it is soluble during the process of binding to an adCAR (an adaptor CAR) via a tagged polypeptide and of subsequently activating the immune cell that expresses the CAR. The specification discloses that this definition does not exclude the possibility that the soluble antigen may be immobilized temporary [temporarily] for example, by temporary binding to a surface of a cell membrane such as a chemokine can do. The soluble antigen is dissolved in a liquid such as in an interstitial fluid of a subject. The specification discloses examples of the soluble antigen: a cytokine, a chemokine, a shed surface receptor, an extracellular matrix remodeling enzyme, a circulating tumor nucleic acid or tumor reactive antibody, including wherein the shed receptor or nucleic acid was present on/in a tumor cell but was shed or secreted, respectively from/by the tumor cell and circulates subsequently in the blood of the subject harboring the tumor cell (page at lines 19-27). The specification discloses an exemplary, but not limiting, laundry list of such soluble antigens (page 9 at lines 31-page 10 at lines 1-20). The specification discloses that the term “epitope” means the part of an antigen that may be recognized and specifically bound by antibodies or antigen binding fragments thereof (page 41 at lines 28-30). The specification discloses that the terms “immune cell” or “immune effector cell” are interchangeable and refer to a cell that may be part of the immune system and executes a particular effector function, such as ab T cells NK cells, NKT cells, B cells, innate lymphoid cells (ILCs), cytokine induced killer cells (CIK), LAK cells gd T cells, Tregs, monocytes or macrophages (paragraph spanning pages 41-42). The specification discloses that the term “subject” refers to an animal (page 42 at line 23). The specification discloses that the term “treatment” as used herein means to reduce the frequency or severity of at least one sign or symptom of a disease (page 42 at lines 19-20).
The specification does not disclose a representative number of soluble, endogenous antigens, including for example, a soluble antigen of a TME of a subject who has cancer, and therefore does not disclose the binding domains that bind to epitopes of such a soluble, endogenous antigen that are comprised in the one or more tagged polypeptides. The specification discloses two antibodies that bind LAP (i.e., latency-associated peptide, a polypeptide that is bound to TGF-b) (Examples).
With regard to antibody binding domains, the art has established that there is no structure/function relationship for the sequence of the antibody CDRs (the complementary determining regions that confer most of the binding interaction of the antibody to its cognate or cross-reactive antigen) and the function of specific binding (see for example, Poosarla et al (Biotechn. Bioeng., 2017, 114(6): 1331-1342), Torres and Casadevall (Trend. Immunol., 2008, 29(2): 91-97), Khan and Salunke (J. Immunol, 2014, 192: 5398-5405), Edwards et al (JMB, 2003, 334: 103-118), Lloyd et al (Protein Engineering, Eng. Design & Selection, 2009, 22(3): 159-168)). Each soluble endogenous antigen, its epitopes, and the structure (sequences) of the antigen binding domains of the tagged polypeptides present in the administered composition of the instant claims must be discovered.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the one or more tagged polypeptides having the functional property of specific binding to epitopes present on a soluble, endogenous antigen in a subject, that are present in the composition that is administered in the claimed method of treatment. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such tagged polypeptides at the time the instant application was filed and hence was not in possession of the method that administers them at the time the instant application was filed.
7. Claims 19-21, 23, 25, 26, 28, 29, 31-33, 35, 36, 38 and 41 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.
“To be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech, Inc. v. Novo Nordisk, A/S, 108F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997) (quoting In re Wright, 999F2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)). In In re Wands 8 USPQ2d 1400 (CAFC 1988), a number of factors are set forth which a court may consider in determining whether a disclosure would require undue experimentation. These factors were set forth as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. All the factors need not be reviewed when determining whether a disclosure is enabling. Amgen, Inc. v. Chugai Pharm. Co., Ltd., 927F2.d 1200, 1213, 18 USPQ2d 1016, 1027 (Fed. Cir. 1991) (noting that the Wands factors “are illustrative, not mandatory. What is relevant depends upon the facts.”).
The specification does not disclose how to use the claimed invention:
A method for treating a subject in need thereof with an immune cell that expresses a chimeric antigen receptor (CAR), the method comprising administering to the subject simultaneously or sequentially the following pharmaceutical agents:
Said immune cell, wherein the CAR expressed thereby contains:
an antigen binding domain (ABD) specific for a tag on one or more tagged polypeptides,
a transmembrane domain (TM),
an intracellular signaling domain; and
said one or more tagged polypeptides, which together contain an antigen binding site specific for epitope A and an antigen binding site specific for epitope B, or multiple antigen binding sites specific for epitope E;
wherein a soluble antigen that is endogenous to the subject comprises both epitope A and epitope B, or sufficient copies of epitope E such that binding of the tagged polypeptide(s) to the soluble antigen and binding of the immune cell to the tagged polypeptide(s) will result in activation of an effector function by the immune cell in the subject, thereby treating the subject (as is recited in instant base claim 36),
and including the limitations recited in the claims depending upon claim 36; or
A method of activating an effector function of an immune cell at the site of an endogenous soluble antigen in the [a] subject, the method comprising contacting the soluble antigen with components (a) and (b) of the combination of claim 15 (as is recited in instant claim 35).
The specification has not enabled the breadth of the claimed invention because the claims encompass a method of treating any condition, disease or disorder in any subject using the recited pharmaceutical agents, or encompass a method of activating an effector function of an immune cell at the site of an endogenous soluble antigen in a subject, wherein the one or more tagged polypeptides have antigen binding sites for one or multiple epitopes that are present on an endogenous soluble antigen in a subject, and wherein in the latter instance, the aim of activating an effector function is for treatment of a subject.
The state of the art is such that it is unpredictable in the absence of appropriate evidence whether the claimed method can be used for treatment or of activating an effector function over its full scope without undue experimentation, as the identity of the endogenous antigen and the epitope(s) thereon must first be discovered and the composition tested for treatment effect for any disease, condition, or disorder in any subject, while the specification discloses one limited ex vivo working example that is not commensurate in scope with the breadth of the claims, (i.e., it creates anti-tag CAR T cells and mixes them with two tagged polypeptide comprising two different antibodies against a soluble antigen, recombinant human LAP (i.e., latency associated peptide, a polypeptide that is bound to TGF-b), and further mixing with LAP to determine that the CAR-T cells could be activated (as visualized by surface expression of CD69 and CD25) (Examples)), while the state of the art indicates that although the adapter CAR platform with the adapter polypeptide having specificity for a tumor-cell expressed antigen (unlike in the instant case wherein the antigen is an endogenous soluble antigen in a subject) is a promising strategy for next-generation immunotherapy [in pancreatic ductal adenocarcinoma], successful clinical translation will require careful target selection and patient-specific parameters to ensure efficacy. This is even more the case with the instantly claimed method that uses an adapter CAR with a tagged polypeptide that binds to a soluble endogenous antigen.
The instant claims are reach-through claims. Undue experimentation would be required to determine operative embodiments within the full breadth of the claimed method.
The specification discloses that the terms “having specificity for”, “specifically binds” or “specific for” with respect to an antigen binding domain of an antibody, of a fragment thereof, or of a CAR refer to an antigen binding domain that recognizes and binds to a specific antigen, but does not substantially recognize or bind other molecules in a sample, or may be cross-species reactive (page 40 at lines 21-24). However, the specification does not disclose a limiting definition for “antigen binding site”, so the limitation may encompass antibody and non-antibody antigen binding sites, e.g., small molecules or other structures that ae able to target an epitope of at least one antigen of interest. The specification discloses that the term “antigen” is intended to include substances that bind to or evoke the production of one or more antibodies, and may comprise but is not limited to proteins, peptides, polypeptides, oligopeptides, lipids, carbohydrates and combinations thereof (paragraph spanning pages 40-41). The specification discloses that the term “soluble antigen” as used herein refers to an antigen that is not immobilized on surfaces, i.e., it is soluble during the process of binding to an adCAR (an adaptor CAR) via a tagged polypeptide and of subsequently activating the immune cell that expresses the CAR. The specification discloses that this definition does not exclude the possibility that the soluble antigen may be immobilized temporary [temporarily] for example, by temporary binding to a surface of a cell membrane such as a chemokine can do. The soluble antigen is dissolved in a liquid such as in an interstitial fluid of a subject. The specification discloses examples of the soluble antigen: a cytokine, a chemokine, a shed surface receptor, an extracellular matrix remodeling enzyme, a circulating tumor nucleic acid or tumor reactive antibody, including wherein the shed receptor or nucleic acid was present on/in a tumor cell but was shed or secreted, respectively from/by the tumor cell and circulates subsequently in the blood of the subject harboring the tumor cell (page at lines 19-27). The specification discloses an exemplary laundry list of such soluble antigens (page 9 at lines 31-page 10 at lines 1-20). The specification discloses that the term “epitope” means the part of an antigen that may be recognized and specifically bound by antibodies or antigen binding fragments thereof (page 41 at lines 28-30). The specification discloses that the terms “immune cell” or “immune effector cell” are interchangeable and refer to a cell that may be part of the immune system and executes a particular effector function, such as ab T cells NK cells, NKT cells, B cells, innate lymphoid cells (ILCs), cytokine induced killer cells (CIK), LAK cells gd T cells, Tregs, monocytes or macrophages (paragraph spanning pages 41-42). The specification discloses that the term “subject” refers to an animal (page 42 at line 23). The specification discloses that the term “treatment” as used herein means to reduce the frequency or severity of at least one sign or symptom of a disease (page 42 at lines 19-20).
Thus the specification discloses that the breadth of the claimed method encompasses treating any disease in any subject (any animal) by administering an adapter CAR (adCAR) and one or more tagged polypeptides having one or more binding domains for one or more epitopes on any endogenous, soluble antigen in a subject, wherein binding of the adCAR platform components will activate an effector function in the administered adCAR-immune cell, which effector function treats the subject having the generic disease, disorder, or condition.
Evidentiary reference Dourlens et al. (BioRxiv, July 9, 2026, pages 1-28, https://doi.org/10/64898/2026.07.03.736407) teach that several factors may influence adaptor CAR platform performance, including CAR expression levels, target antigen abundance, adapter concentration, donor-to-donor variability, adapter-binding kinetics, degree of labeling, the adaptor CAR affinity for the labeling moiety, as well as yet unidentified parameters (page 15). Dourlens et al. teach that differences in adapter CAR expression can influence the overall response, which influences functional avidity. The latter reflects the combination of multiple receptor-ligand interactions and is influenced by CAR expression, signaling strength, and tumor antigen density. Tuning CAR affinity can in turn impact T cell expansion and persistence, while T cell function is influenced by donor-dependent factors such as subset composition, differentiation state, transduction efficiency, tonic signaling, and overall cellular fitness and exhaustion (page 15). Dourlens et al. teach “In vivo validation would also be essential to confirm tumor-specific killing, safety and potential immunogenicity due to repeated adapter injection” (page 16). Dourlens et al. further teaches “…successful clinical translation will require careful optimization of target selection, dosing strategies, and patient-specific parameters to ensure …efficacy (last sentence on page 17). See entire reference.
Thus, the evidentiary reference speaks to unpredictability in the art of activating an effector function of an adCAR T or other immune cell, including to treat a condition. The evidentiary reference teaches that system design as well as factors inherent in vivo in different subjects can influence performance at least for treating a solid tumor and vivo validation is necessary. Contrast this with the aforementioned one ex vivo working example that is not commensurate in scope with the breadth of the claims. (The example creates anti-tag CAR T cells and mixes them with two tagged polypeptides comprising two different antibodies against a soluble antigen, recombinant human LAP (i.e., latency associated peptide, a polypeptide that is bound to TGF-b), and further mixing with LAP to determine that the CAR-T cells could be activated in vitro (as visualized by surface expression of CD69 and CD25) (Examples)). In addition, it is also unpredictable which species of immune cells and in combination with which species of soluble endogenous antigens would be sufficient to treat the conditions, diseases, or disorders encompassed by the method recited in the instant claims, including where the CAR-immune cells are activated in vivo.
There is insufficient guidance in the specification as to how to use the instant invention. Undue experimentation would be required of one skilled in the art to practice the instant invention. See In re Wands 8 USPQ2d 1400 (CAFC 1988).
8. 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.
9. 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.
10. Claims 19, 20, 31, 35, 36 and 41 are rejected under 35 U.S.C. 102(a)(i) as being anticipated by Darowski et al. (mAbs, 4/17/19, 11:4, pages 621-631, of record) as evidenced by Ho et al. (Cancer Epidemiol. Biomarkers Pre., 2006, 15(9): 1751, of record), Bryan et al. (JBC, 2015, 112: 1052-1058, of record), and Perez-Torres et al. (Exp. Cell. Res., 2008, 314: 2907-2918, of record), and by an admission in the specification on page 9 at lines 19-21.
Independent base claim 36 recites:
A method for treating a subject in need thereof with an immune cell that expresses a chimeric antigen receptor (CAR), the method comprising administering to the subject simultaneously or sequentially the following pharmaceutical agents:
Said immune cell, wherein the CAR expressed thereby contains:
an antigen binding domain (ABD) specific for a tag on one or more tagged polypeptides,
a transmembrane domain (TM),
an intracellular signaling domain; and
said one or more tagged polypeptides, which together contain an antigen binding site specific for epitope A and an antigen binding site specific for epitope B, or multiple antigen binding sites specific for epitope E;
wherein a soluble antigen that is endogenous to the subject comprises both epitope A and epitope B, or sufficient copies of epitope E such that binding of the tagged polypeptide(s) to the soluble antigen and binding of the immune cell to the tagged polypeptide(s) will result in activation of an effector function by the immune cell in the subject, thereby treating the subject.
Independent claim 35 recites:
A method of activating an effector function of an immune cell at the site of an endogenous soluble antigen in the subject, the method comprising contacting the soluble antigen with components (a) and (b) of the combination of claim 15.
Claim interpretation: The specification discloses that the term “subject” refers to an animal (page 42 at line 23). The specification discloses that the term “treatment” as used herein means to reduce the frequency or severity of at least one sign or symptom of a disease (page 42 at lines 19-20). The specification discloses examples of the soluble antigen: a cytokine, a chemokine, a shed surface receptor, an extracellular matrix remodeling enzyme, a circulating tumor nucleic acid or tumor reactive antibody, including wherein the shed receptor or nucleic acid was present on/in a tumor cell but was shed or secreted, respectively from/by the tumor cell and circulates subsequently in the blood of the subject harboring the tumor cell (page at lines 19-27). The specification discloses an exemplary laundry list of such soluble antigens (page 9 at lines 31-page 10 at lines 1-20). As the instant claims recite “said one or more tagged polypeptides, which together contain…multiple antigen binding sites specific for epitope E”, the claims are being interpreted as the one or more tagged polypeptides being bivalent or monovalent, wherein in either instance, multiple copies of the tagged polypeptide is administered. The recitation of “epitope A”, “epitope B”, “epitope E”, ‘epitope C”, and “epitope D” indicates generic placeholders for particular different epitopes of an antigen. The open transitional phrase “comprising” opens the claims to encompass other non-recited steps and/or ingredients.
Darowski et al. teach a combination of a modified (adapter) CAR-T cell (that comprises an antigen binding domain specific for a tag on a polypeptide, a transmembrane (TM) region, and an intracellular signaling domain) and a tagged polypeptide (an adapter molecule) that comprises an antigen binding domain for a tumor associated antigen, for example, MSLN (mesothelin), EpCAM, or EGFR. Darowski et al. teach that some of the adapter polypeptides are bivalent or multi-specific, the latter with regard to targeting a variety of antigens simultaneously. Darowski et al. exemplify administering the adapter CAR plus adapter polypeptides in vivo and treating a cancer in murine models. (See entire reference, particularly Table 1, Fig. 1, Fig. 2, paragraph spanning the last paragraph on page 622-623).
The admission in the specification on page 9 at lines 19-21 is that the soluble antigen may be a shed surface receptor.
Evidentiary reference Ho et al. teaches that mesothelin is shed from tumor cells (see entire reference).
Evidentiary reference Bryan et al. teaches that epCAM is shed form urothelial bladder cancer cells (see entire reference).
Evidentiary reference Perez-Torres et al. teaches that epidermal growth factor (EGFR) is shed from malignant cancer cells (see entire reference).
Thus, the evidentiary references teach that the shed tumor antigens are endogenous soluble antigens (as well as tumor cell surface-expressed antigens) of the subject having cancer.
With regard to the newly recited limitation of ‘sufficient copies of an epitope such that binding of the tagged polypeptide(s) to the soluble antigen and binding of the immune cell to the tagged polypeptide(s) will result in activation of an effector function by the immune cell’, although the art reference does not teach this limitation, it does teach that the administration of the adapter CAR plus tagged polypeptide adapter molecule produces activation of the CAR-T cell effector function and a treatment effect in vivo in the presence of soluble as well as cell surface antigen. Since the Patent Office does not have the facilities for examining and comparing the method of the instant invention to those of the prior art, the burden is on Applicant to show a distinction between the method of the instant invention and that of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
Instant claim 19 is included in this rejection because the art reference teaches CD3zeta is a signaling domain in the CAR. CD3zeta inherently comprises three distinct ITAMS in its cytoplasmic domain (see evidentiary reference A.M. Becker (2009, https://hdl.handle.net/2152.5/304, 2 pages).
Instant claim 20 is included in this rejection because the antigens that are shed from tumor cells are present at least for a time in the tumor microenvironment of the subject who has cancer.
Instant claim 31 is included in this rejection because the art reference discusses administration of the CAR-T cell and the adapter molecule (the tagged polypeptide) separately, e.g., page 625 at column 1 at the 2nd full paragraph (i.e., targeting the antigen with the adaptor resulted in effective recruitment of the adapter-specific CAR-T cells).
Instant claims 32 and 33 are included in this rejection because the art reference teaches that the immune cell is a T cell and the effector function is cytolytic (cytotoxic) activity against the tumor cells.
11. The Examiner notes the following disclosure in the instant specification:
The specification on page 2 at lines 18-28 discloses that it was surprisingly found that an immune cell expressing an adapter CAR that specifically binds to an adapter that binds specifically to a soluble antigen such as a cytokine that may be present , e.g., in a TME can be activated when said adapter CAR binds the adapter that is bound to the soluble antigen. The essential requirement for the activation of the immune cell expressing the adapter CAR is the soluble antigen mediated dimerization of the adapter CAR. This finding is unexpected as the use of an additional, non-covalent bound spacer molecule, i.e., the adapter, is inserted between the antigen and the CAR expressed on the surface of the immune cell, shifting the CAR system to a more instable system as compared to a CAR that directly binds the soluble antigen. Nonetheless and unexpectedly, this adapter CAR system is mechanically rigid enough to transmit tensile force to the CARs intracellular signaling domains when the adapter and the soluble antigen fulfill the criteria as disclosed herein.
Although IDS reference Chang et al. teaches that ligand-induced CAR receptor dimerization is a requirement for activation of CAR-T cells binding to the soluble antigen TGF-b, it would not be expected that a soluble antigen targeted with an adapter CAR would induce the same ligand-induced CAR receptor dimerization that precedes activation, as it was unpredictable that the complex of CAR-T cell bound to an adapter polypeptide bound in turn to a soluble antigen would be necessarily rigid enough to induce ligand-dependent CAR receptor dimerization and subsequent activation of the CAR-T cell. Thus, an obviousness type rejection has not been made extending the teachings of Chang et al. regarding binding of CAR-T cells to the soluble antigen TGF-b or extending the teachings of the art regarding binding of adCAR-T cells via an adaptor polypeptide to a cell surface expressed antigen to the instantly claimed invention.
The relevant teachings of Chang et al. are here:
Chang et al. (Nature Chemical Biology, 3/2018, 14: 317-324) teaches that CAR-T cells can be engineered to respond robustly to soluble ligands, provided that the ligands are capable of mediating CAR dimerization, and further teaches that CAR responses to soluble ligands can be tuned by adjusting the mechanical coupling of the CAR’s extracellular ligand-binding domain and its intracellular signaling domains, consistent with a mechano-transduction model of CAR signaling (page 317 at the second full paragraph at column 2). Chang et al. teach that ligand-mediated receptor dimerization triggers CAR signaling, receptor pre-dimerization in the absence of ligand is not sufficient for CAR signaling, and ligand binding results in active, actin-dependent changes in CAR distribution, with the resulting CAR clusters strongly colocalizing with ZAP70, and receptor dimerization exerts tensile force on the CARs that are brought together, reminiscent of force-actuated TCR signaling. The reference teaches that such factors as lengthening the extracellular spacer affected signaling threshold and intensity but requiring more antigen. The authors conclude that the dynamic process of receptor dimerization and the mechanical coupling between the ligand binding and signaling domains of the CAR are both important for signal transduction. The soluble ligand must be able to bring together two or more CARs, the CARs ligand binding affinity must be strong enough to withstand the tensile force necessary for CAR activation, and both the soluble ligand and the CARs involved must be mechanically rigid enough to transmit tensile force to the CARs intracellular signaling domains (page 322-323).
12. Claim 26 is objected to because of the following informalities: The claim should recite “a” polynucleotide encoding the chimeric antigen receptor in the immune cell further comprises…”. Appropriate correction is required.
13. Claim 28 is objected to because of the following informality: The claim should recite “a” polynucleotide encoding … at the second line of the claim. Appropriate correction is required.
14. Claim 35 is objected to because of the following informality: Claim 35 recites “with components (a) and (b) of the combination of claim 15” whereas claim 15 recites the components as “a)” and “b)”. Appropriate correction is required.
15. Claim 35 is objected to because of the following informality: Claim 35 recites “A method of activating an effector function of an immune cell at the site of an endogenous soluble antigen in the subject”, whereas it should recite “a” subject. IN addition, claim 35 does not recite that the immune cell whose effector function is activated is the CAR-immune cell that is administered. Appropriate correction is required.
16. No claim is allowed.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the Examiner’s supervisor, MISOOK YU can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights