DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s response filed on 7/7/2026 is acknowledged. Claim 45 is new. Claims 24, 26-32, 35-36, 38 and 45 are pending. Claims 1-23, 25, 33-34, 37 and 39-44 are canceled. Claims 24, 35 and 36 are amended
3. Claims 24, 26-32, 35-36, 38 and 45 are under examination.
Rejections Withdrawn
4. All rejections except those maintained below are withdrawn in view of applicant’s amendments.
Rejections Maintained
Double Patenting
5. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
6. Claims 24, 26-32, 35-36, 38 and new claim 45 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31, 40-48 and 50-52 of copending Application No. 17/801, 293. Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 31, 40-48 and 50-52 of copending Application No. 17/801, 293 disclose a method of treating autoimmune disease, or infectious disease in a subject, the method comprising administering to a subject a glucocorticoid receptor (GR) modulating agent at a dose equivalent to about at least 6 mg/kg human equivalent dose (HED) of dexamethasone base, isolating a population of NKT cells from the subject or from a sample derived from the subject-optionally wherein the step of isolating is performed: i) at least18 hours after glucocorticoid administration; or ii) between18 hours and 13 days after glucocorticoid administration, administering a therapeutically effective dose of the isolated NKT cells to the subject, wherein a glucocorticoid receptor (GR) modulating agent is a glucocorticoid and is administered at a dose equivalent to about 6-45 mg/kg or 6-12 mg/kg human equivalent dose (HED) of dexamethasone base, the glucocorticoid is selected from dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, prednylidene, cortisone, budesonide, betamethasone, flumethasone and beclomethasonek, wherein the autoimmune diseases is multiple sclerosis, or type 1 diabetes, the infectious disease is influenza virus, HIV or hepatitis, wherein the NKT cells are modified to express a CAR.
Applicant’s Arguments
The response states that the effective filing date of the present application is April 1, 2017, while the effective filing date of US Application No. 17/801,293 is February 28, 2020. See MPEP § 804(B)(1)("If a 'provisional' nonstatutory double patenting rejection is the only rejection remaining in an application having the earliest effective U.S. filing date (including any benefit claimed under 35 U.S.C. 120, 121, 365(c), or 386(c)) compared to the reference application(s), the examiner should withdraw the rejection in the application having the earliest effective U.S. filing date and permit that application to issue as a patent...").
Examiner’s Response
Applicant’s arguments have been carefully considered but are not persuasive because the rejection is not an only rejection remaining in the application as this time.
7. Claims 24, 26-32, 35-36, 38 and new claim 45 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 9, 14, 21, 23, 25, 31 and 40-42 of copending Application No. 18/683,814. Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of copending application disclose a method of treating autoimmune disease, or infectious disease in a subject, the method comprising administering to a human subject a glucocorticoid-receptor (GR) modulating agent at a dose equivalent to about at least 6 mg/kg human equivalent dose (HED) of dexamethasone base; isolating a population of natural killer T-cell like cells (NKT-like cells) from the subject, and administering the NKT cells to the subject,
wherein the glucocorticoid-receptor (GR) modulating agent is a glucocorticoid, the glucocorticoid is dexamethasone, hydrocortisone, methylprednisolone, prednisone,
wherein the glucocorticoid is administered at a dose equivalent to about: i) at least 6-12 mg/kg human equivalent dose (HED) of dexamethasone base; ii) at least 6 mg/kg human equivalent dose (HED) of dexamethasone base; iii) at least 12 mg/kg human equivalent dose (HED) of dexamethasone base; iv) at least 15 mg/kg human equivalent dose (HED) of dexamethasone base; v) at least 21 mg/kg human equivalent dose (HED) of dexamethasone base; vi) at least 24 mg/kg human equivalent dose (HED) of dexamethasone base; vii) 15 mg/kg human equivalent dose (HED) of dexamethasone base; viii) 24 mg/kg human equivalent dose (HED) of dexamethasone base; or ix) 45 mg/kg human equivalent dose (HED) of dexamethasone base,
wherein the NDT cells are modified to express a CAR,
wherein the subject has, or has been diagnosed with a disease selected from the group consisting of: cancer, autoimmune disease, or infectious disease,
wherein the autoimmune disease is selected from the group consisting of: multiple sclerosis, systemic sclerosis, amyotrophic lateral sclerosis, type 1 diabetes mellitus, scleroderma, pemphigus, and lupus; or (b) the infectious disease is HIV or a disease resulting from infection with a coronavirus, such as COVID-19.
Applicant’s Arguments
The effective filing date of the present application is April 1, 2017, while the effective filing date of US Application No. 18/683,814 is September 1, 2021. The present application is the earlier- filed application, and the provisional obviousness-type double patenting rejection should be withdrawn once the present claims are otherwise allowable.
Examiner’s Response
Applicant’s arguments have been carefully considered but are not persuasive because the instant rejection is not an only rejection remaining in the application as this time.
New Grounds of Rejection
Claim Rejections - 35 USC § 112
8. 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.
9. Claims 24, 26-32, 35-36, 38 and 45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a subject having an infectious disease selected from the group consisting of HIV, influenza and hepatitis, the method comprising administering to the subject CAR T cells or CAR NK cells, does not reasonably provide enablement for a method of treating a subject having an autoimmune disease selected from the group consisting of systemic lupus erythematosus, multiple sclerosis, arthritis, and type 1 diabetes, the method comprising administering to the subject CAR T cells or CAR NK cells. 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
''Factors to be considered in determining whether a disclosure would
require undue experimentation have been summarized by the board in Ex
parte Forman. They include (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.''
The nature of the invention
Independent claim 24 is drawn to a method of preconditioning before administering CAR therapy in a patient suffering from an autoimmune disease or an infectious disease, the method comprising:
administering to the patient dexamethasone or another glucocorticoid at a dose that is effective to cause lymphodepletion and/or cause ablation of secondary lymphatic germinal centers prior to administering CAR therapy,
wherein the method does not include the administration of a chemotherapeutic agent for a duration of more than 1 day;
wherein the dose of dexamethasone or another glucocorticoid that is effective to cause lymphodepletion and/or cause ablation of secondary lymphatic germinal centers is a human equivalent dose (HED) of at least 5 mg/kg dexamethasone or a dose of another glucocorticoid that is equivalent to at least 5 mg/kg dexamethasone;
wherein the CAR therapy comprises administration of CAR-T cells or CAR-natural killer (NK) cells to the patient;
wherein the autoimmune disease is selected from systemic lupus erythematosus, multiple sclerosis, arthritis, and type 1 diabetes; and wherein the infectious disease is selected from human immunodeficiency virus, influenza, and hepatitis.
The claim is interpreted to comprise two steps: 1) preconditioning, and 2) CAR therapy. Accordingly, the nature of the invention is adoptive cellular therapy (ACT) for systemic lupus erythematosus, multiple sclerosis, arthritis, type 1 diabetes, human immunodeficiency virus, influenza or hepatitis.
The invention is in a class of invention, which the CAFC has characterized as ''the unpredictable arts such as chemistry and biology.'' Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The breadth of the claims
The claims encompass treating systemic lupus erythematosus, multiple sclerosis, arthritis, type 1 diabetes, human immunodeficiency virus, influenza or hepatitis using any CAR T cells or CAR-NK cells, in combination with a high dose of dexamethasone or another glucocorticoid (i.e. a dose that is equivalent to at least 5 mg/kg, 9-12 mg/kg or 5-26 mg/kg dexamethasone).
Quantity of experimentation
The quantity of experimentation in this area is extremely large in view of the breadth of the claims and the unpredictability of treating autoimmune disease and infectious disease, in particular by CAR-T cells and CAR-natural killer (NK) cells in combination with a high dose of dexamethasone or another glucocorticoid.
The state of the prior art and the unpredictability of the art
Chen et al. (Journal of Immunology Research, 2019, Article ID 5727516, 9 pages) teaches that by using the idea of CAR-T cell treatment in tumors, CAR-T cell derived immunotherapies, chimeric autoantibody receptor T (CAAR-T) cells, and CAR regulatory T (CAR-T) cells bring new hope of treatment choice for AIDs (autoimmune diseases) (abstract). Using CAAR-T cells to treat antibody-mediated AIDs, two preconditions are needed. One is that the sequence and molecular structure of the specific antigens are clear to guarantee the engineered key epitopes of the CAAR are correct to make sure the engineered epitopes can be recognized by cognate autoantibodies from patients. The other is the role of autoantibodies in the pathogenesis of a disease should be well investigated to make sure their pathogenicity (page 3, right column). Chen et al. teaches that regulatory T cells (Tregs) also play a critical role in regulating the immune system by inhibiting the function of immune cells to keep immunologic self-tolerance and immune homeostasis, and an AID will occur when the specific transcription factor Forkhead box protein P3 (Foxp3) of Tregs is mutated or the CD4+CD25+ T cells are eliminated. Therefore, applying Treg therapy in AIDs after being engineered to CAR-Tregs having antigen specificity may be a new choice (page 5, right column). Using CAR-T cells to treat AIDs, CARs can be tailored according to specific antigens or antibodies in different AIDs, so CAR-T cells have unique specificity (page 6, column 2). Nevertheless, finding the specific antigens to construct antigen specific CARs is not easy in some disease conditions (page 6, column 2). Chen et al. teaches that for the use of CAR-Tregs, attention should be paid to several issues. On the on hand, the immunosuppressive phenotype of Tregs will change after losing Foxp3 expression under an inflammatory microenvironment, from the immunosuppressive state to effector cells that aggravate disease symptoms (page 7, column 1).
Fransson et al (Journal of Neuroinflammation, 2012, 9:112) teaches CAR/FoxP3-engineered T regulatory cells (Treg) target the CNS and suppress experimental autoimmune encephalomyelitis (EAE) upon intranasal delivery (abstract), wherein the Treg cells are engineered to express a CAR targeting myelin oligodendrocyte glycoprotein (MOG). Although EAE is the murine model of MS, and Fransson et al. shows that MOG-specific CAR Treg cells can treat EAE in animal model, there is no evidence indicating any CAR T cells other than CAR Treg, and CAR NK cells can treat multiple sclerosis.
Moreover, there is no evidence indicating any CAR T cells and CAR NK cells can treat systemic lupus erythematosus, arthritis, and type 1 diabetes.
Working examples and guidance in the specification
Example 1 shows that T cell immunotherapies bind to the germinal center and marginal zone regions of the spleen and secondary lymphatics and the binding is reduced by dexamethasone dosing.
Example 2 shows that immunosuppressant reduction of the sites in the secondary lymphatics wherein cellular immunotherapies are bound and sequestered.
Example 3 shows that immunosuppressant lymphodepletion in mice, rats, and humans 36-48 hours after acute administration of dexamethasone, with neutrophil, RBC, platelet and stem cell sparing properties.
Example 4 compares acute 12 mg/kg dexamethasone base HED to a standard Cy (cyclophosphamide) Flu (fludarabine) preconditioning regimen.
Example 5 shows immunocompetent mouse model of multiple myeloma. Example 6 lists various conditions intended to be treated.
Example 7 discloses post-surgical treatment of solid tumors with NTLA and cellular immunotherapy to prevent relapse. Example 7 appears to be prophetic as the example mentions “NTLA preconditioned patients will have similar or better anti-tumor effect…”.
Example 8 discloses treatment of post-surgical breast tumors in mice. Example 8 appears to be prophetic as the example states “Mice survival plot will be made to compare the survival benefit between different treatments” and mentions “expected outcome”.
Example 9 discloses treatment of post-surgical solid tumors in mice. Example 9 appears to be prophetic as the example states “Mice survival plot will be made to compare the survival benefit between different treatments” and mentions “expected outcome”.
Example 10 discloses treatment of patients with solid tumors. Example 10 appears to be prophetic as the example states “The NTLA preconditioned patients will have similar or better anti-tumor effect…”.
Example 11 discloses treatment of patients with leukemias or lymphomas or myelomas. Example 11 appears to be prophetic as the example states “The NTLA preconditioned patients will have similar or better anti-tumor effect…”.
Example 12 discloses treatment of patients with autoimmune diseases with dexamethasone alone. No cellular adoptive therapy was administered.
Example 13 discloses treatment of residual HIV with dexamethasone alone. No cellular adoptive therapy was administered.
Example 14 discloses treatment of germinal center lymphoma, for example Burkitts lymphoma with dexamethasone. No cellular adoptive therapy was administered.
There is no working examples and guidance on making any specific CAR T or CAR NK cells for treatment of an autoimmune disease.
As evidenced by Chen and Fransson, for CAR-T cells and CAR-NK cells to treat an autoimmune disease or infectious disease, CARs must be designed to recognize a specific antigen that is involved in the disease (a disease-relevant antigen). In the instant case, the specification does not identify any specific antigens that could be targeted by CAR T or CAR NK cells for treatment of an autoimmune disease. The prior art does not supplement the missing information. Neither the specification nor the prior art discloses the CAR specificity. Therefore, the specification does not teach how to make and use CAR T or CAR NK cells to treat an autoimmune disease.
While it is understood that the absence of working examples should never be the sole reason for rejecting a claims as being broader than an enabling disclosure, the criticality of working examples in an unpredictable art such as treating autoimmune disease and infectious disease with adoptive cellular therapy is required for practice of the claimed invention.
Level of skill in the art
The level of skill in the art is deemed to be high.
Conclusion
Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of the art, the large quantity of research required to define these unpredictable variables, the lack of working examples, and guidance on using CAR T cells and CAR NK cells in treating systemic lupus erythematosus, multiple sclerosis, arthritis, and type 1 diabetes, and the negative teachings in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation to perform the method of the claim as broadly written.
Applicant’s Arguments
The response states that applicant previously submitted articles dated close to or earlier than the 2017 priority date of the instant application. Data from in vitro or animal models that are recognized as correlating to a specific condition, such as the experiments described in the articles below, can support enablement. See Edwards Lifesciences AG v. CoreValve, Inc. 699 F.3d 1305, 1310 (Fed. Cir 2012); MPEP §2164.02; see In re Brana, 51 F.3d at 1562 (indicating that requiring human data for enablement "confuses the requirements under the law for obtaining a patent with the requirements for obtaining government approval to market a particular drug for human consumption"). The references listed below were submitted in the IDS dated March 18, 2025, or the IDS dated August 5, 2025.
Autoimmune Disease
Jethwa et al., Clinical Immunology (2014); 150: 51-63, describes using adoptive T-cell immunotherapy including chimeric antigen receptor-T cells to suppress unwanted autoimmune, inflammatory, and allograft-targeted immune responses. Id. at Introduction. Jethwa states that pre-clinical studies have demonstrated that "adoptive transfer of purified CD4+ CD25+ Tregs can inhibit or prevent disease in a range of models of autoimmune illness. These include, but are not restricted to systemic lupus erythematosus, inflammatory bowel disease, autoimmune encephalomyelitis, type 1 diabetes, autoimmune hepatitis and collagen-induced arthritis." Id. at page 53 (internal citations omitted) (emphasis on claim terms added). Jethwa describes a study using CAR T-cells in an experimental autoimmune encephalomyelitis ("EAE") mouse model for multiple sclerosis (page 56). Jethwa concludes that, "Since regulatory T-cells constitute primary effectors of peripheral tolerance, genetic harnessing of the antigen-dependent immunosuppressive capability of these cells is a logical potential strategy to control disease types that are driven by pathologic immune responses." Id. at 59. Thus, Jethwa supports using CAR therapy as a treatment for various autoimmune diseases.
Additional articles support the use of CAR therapy in, e.g., diabetes by way of preclinical or animal models. Barrett, J Immunol. (2015), 195(3):755-761 states that "The principles of synthetic engineering have been applied to Tregs, as for example, CAR Tregs show promise in preclinical models of autoimmunity." Barrett states "adoptive transfer of Tregs can prevent lethal GVHD and autoimmune diabetes in mice."
Yeh, Front. Immunol. (2017), 8:1313 describes preclinical data supporting the use of autoantigen-specific CAR-T cells as a therapy for type 1 diabetes. See id. at page 2 ("Islet cell antigen-reactive Tregs, isolated from BDC2.5 TCR transgenic mice, could be expanded in vitro, and following adoptive transfer, migrate to the pancreatic draining lymph node/nodes. These Treg prevent and reverse autoimmune diabetes in non-obese diabetic (NOD) mice.").
Chang, Trends Mol Med. (2017 May), 23(5): 430-450, discusses uses of CAR therapy in pre-clinical models of autoimmune and infectious diseases. Chang describes studies of using CAR-T cells against pemphigus vulgaris (PV) and using CAR-T cells in an in vivo mouse model of multiple sclerosis to ameliorate experimental autoimmune encephalomyelitis (EAE, murine model of multiple sclerosis) by inhibiting the activity of multiple autoreactive T cell clones. Id. at pages 16-17.
Infectious Disease
With respect to infectious diseases, the Examiner acknowledges that CAR-T cells were used to treat HIV and influenza virus, citing the previously submitted Qian et al. (2022) reference and the previously submitted Tabot et al. (2013) reference. See Non-Final Office Action, dated April 8, 2025, at page 22. Regarding HIV infection, Zhen, Molecular Therapy (2015), 23(8):1358-1367 further indicates that CAR-modified HSPCs differentiate into functional T cells as well as natural killer (NK) cells in vivo in humanized mice and that these cells are resistant to HIV infection and suppress HIV replication. The above-referenced Barrett article states, "It is interesting to note from an historical perspective that some of the first forms of ACT involving gene-modified T cells were conducted almost two decades previously in patients with advanced HIV-1/AIDS," indicating that the results of these HIV trials informed current concepts of CAR T cells in the field of cancer. See Barrett at page 2.
Krebs, Gastroenterology (2013), 145:456-465 describes an animal study in
immunocompetent mice suggesting that S-CAR-engineered T cells could be pursued to treat hepatitis B virus.
Sautto et al., Gut (2016), 65:512-523 describes CAR-T cells directed against hepatitis C virus, stating "adoptive transfer of anti-HCV/E2 CARs-grafted T cells represents a promising new therapeutic tool." The above-referenced Chang article also states, regarding CAR therapy to combat infectious and autoimmune diseases in preclinical models "Antiviral approaches have targeted Hepatitis B, Hepatitis C, and HIV infections, where virus-infected cells can be distinguished by surface presentation of specific viral proteins" (page 16).
The foregoing review of the previously submitted articles evidences that at the time of the priority date of the instant application, many autoimmune and infectious diseases were recognized by those skilled in the art as amenable to treatment with CAR therapy, including systemic lupus erythematosus, multiple sclerosis, arthritis, type 1 diabetes, HIV, influenza, and hepatitis. Thus, each of the diseases recited in claim 24 was recognized in the art as amenable to CAR therapy, and one of ordinary skill could have practiced the method of claim 24 without undue experimentation in view of the present disclosure and knowledge in the art. Applicant respectfully submits that the present claims are sufficiently enabled.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive because applicant has not shown that systemic lupus erythematosus, multiple sclerosis, arthritis, and type 1 diabetes can be treated by any CAR-T cells or CAR-NK cells.
Jethwa et al (submitted by applicant in the response) states “Pre-clinical studies have demonstrated that adoptive transfer of purified CD4+ CD25+ Tregs can inhibit or prevent disease in a range of models of autoimmune illness. These include, but are not restricted to systemic lupus erythematosus [36], inflammatory bowel disease [37], autoimmune encephalomyelitis [38], type 1 diabetes [39], autoimmune hepatitis [40] and collagen-induced arthritis [41]” (page 53, last paragraph). However, these studies used purified CD4+ CD25+ Treg cells, not CAR-T cells or CAR-NK cells, as evidenced by citations [36]-[41].
Citation 36 (Scalapino et al. J Immunol, 2006, 177: 1451-1459) discloses that thymic-derived Tregs may have a significant role in the control of autoimmunity in lupus-prone B/W mice, and augmentation of these cells may constitute a novel therapeutic approach for systemic lupus erythematosus. However, Citation 36 does not mention CAR-T cells or CAR-NK cells.
Citation 37 (Mottet et al., J Immunology, 2003, 170:3939-3943) teaches treating intestinal inflammation with CD4+CD25+ Treg cells. However, Citation 37 does not mention CAR-T cells and CAR NK cells.
Citation 38 (Kohm et al. J Immunology, 2002, 169:4712-4716) teaches that adoptive transfer of CD4+CD25+ Treg cell line that is specific to MOG35-55 conferred significant protection from clinical experimental autoimmune encephalomyelitis. Citation 38 does not disclose CAR-T cells and CAR-NK cells.
Citation 39 (Mukherjee et al. J Autoimmunity, 2003, 21:221-237) disclose that Treg cells generated in response to insulin B:9–23 peptide prevent adoptive transfer of diabetes by diabetogenic T cells. Citation 39 does not disclose CAR-T cells and CAR-NK cells.
Citation 40 (Lapierre et al. Hepatology, 2013, 57:217-227) teaches using ex vivo expanded CXCR3+ Tregs to treat autoimmune hepatitis in murine model. However, Citation 40 does not disclose CAR-T cells and CAR-NK cells.
Citation 41 (Morgan et al. Arthritis & Rheumatism, 2005, 52(7): 2212-2221) teaches treating collagen-induced arthritis using CD25+ Treg cells. Citation 40 does not disclose CAR-T cells and CAR-NK cells.
Jethwa further describes a study using CAR T-cells in an experimental autoimmune encephalomyelitis ("EAE") mouse model for multiple sclerosis [59] (page 56, paragraph 1). In this study, CAR-Treg cells were used as evidenced by Citation 59 (Fransson et al. J Neuroinflammation, 2012, 9:112). Citation 59 (Fransson et al) teaches CAR/FoxP3-engineered T regulatory cells (Treg) target the CNS and suppress experimental autoimmune encephalomyelitis (EAE) upon intranasal delivery (abstract), wherein the Treg cells are engineered to express a CAR targeting myelin oligodendrocyte glycoprotein (MOG). Although EAE is the murine model of MS, and Fransson et al. shows that MOG-specific CAR Treg cells can treat EAE in animal model, there is no evidence indicating any CAR T cells other than CAR Treg, and any CAR NK cells can treat multiple sclerosis. Moreover, there is no evidence indicating any CAR T cells and CAR NK cells can treat systemic lupus erythematosus, arthritis, and type 1 diabetes.
Barrett et al (submitted by applicant in the response) states “as the adoptive transfer of Tregs can prevent lethal GVHD and autoimmune diabetes in mice (8, 9)”. In this sentence, Barrett meant Treg cells, not CAR-T cells, as evidenced by citations 8 and 9. Barrett states “Specifically, modifying mouse Tregs with a CAR targeting myelin basic protein specific T cells protected against autoimmune encephalitis, and the concept is being pursued for colitis and diabetes targeting antigens in the colon and pancreatic islet, respectively (16-18)”. It appears that Citation 17 used Treg cells (not CAR-T cells) to treat rheumatoid arthritis in animal model. Citation 18 is Jethwa et al., which was discussed earlier. Citation 17 discloses “In murine models, introduction of a chimeric immune receptor (CIR) into Treg cells prevented experimental autoimmune encephalomyelitis and experimental-induced colitis (page 661, last paragraph). There is no evidence indicating diabetes can be treated with any CAR T cells or CAR NK cells. There is no evidence indicating any CAR T cells and CAR NK cells can treat arthritis.
Yeh et al (submitted by applicant in the response) describes the use of type-1 diabetes-related autoantigen-specific Treg cells expressing a TCR that is specific for GAD555-567. No animal studies were carried out. No CAR-T and CAR-NK cells were used.
Chang et al (submitted by applicant in the response) discloses an in vivo mouse model of multiple sclerosis to ameliorate experimental autoimmune encephalomyelitis (EAE, murine model of multiple sclerosis) by inhibiting the activity of multiple autoreactive T cell clones. As evidenced by Citations 144 and 145 (Fransson et al) of Chang et al, CAR-Treg cells were used in these experiments. The instant claims are not limited to CAR-Treg cells. There is no evidence indicating CAR T cells (other than CAR-Treg) and CAR NK cells can treat multiple sclerosis.
In summary, the evidentiary documents show that before the filing date of the claimed invention, specific CAR-T cell was used in treating influenza virus, HIV, hepatitis B in animal models, and specific CAR-Treg cell was used in treating multiple sclerosis in animal model (Jethwa, Fransson) and Chang. However, the specification has not enabled the full scope of the claimed invention.
Claim Rejections - 35 USC § 112
10. Claims 24, 26-32, 35-36, 38 and 45 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical 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 applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
Independent claim 24 is drawn to a method of preconditioning before administering CAR therapy in a patient suffering from an autoimmune disease or an infectious disease, the method comprising:
administering to the patient dexamethasone or another glucocorticoid at a dose that is effective to cause lymphodepletion and/or cause ablation of secondary lymphatic germinal centers prior to administering CAR therapy,
wherein the method does not include the administration of a chemotherapeutic agent for a duration of more than 1 day;
wherein the dose of dexamethasone or another glucocorticoid that is effective to cause lymphodepletion and/or cause ablation of secondary lymphatic germinal centers is a human equivalent dose (HED) of at least 5 mg/kg dexamethasone or a dose of another glucocorticoid that is equivalent to at least 5 mg/kg dexamethasone;
wherein the CAR therapy comprises administration of CAR-T cells or CAR-natural killer (NK) cells to the patient;
wherein the autoimmune disease is selected from systemic lupus erythematosus, multiple sclerosis, arthritis, and type 1 diabetes; and wherein the infectious disease is selected from human immunodeficiency virus, influenza, and hepatitis.
The claims encompass using a genus of CAR-T cells and CAR-NK cells to treat systemic lupus erythematosus, multiple sclerosis, arthritis, type 1 diabetes, human immunodeficiency virus, influenza or hepatitis.
Chen et al. (Journal of Immunology Research, 2019, Article ID 5727516, 9 pages) teaches that by using the idea of CAR-T cell treatment in tumors, CAR-T cell derived immunotherapies, chimeric autoantibody receptor T (CAAR-T) cells, and CAR regulatory T (CAR-T) cells bring new hope of treatment choice for AIDs (autoimmune diseases) (abstract). Using CAAR-T cells to treat antibody-mediated AIDs, two preconditions are needed. One is that the sequence and molecular structure of the specific antigens are clear to guarantee the engineered key epitopes of the CAAR are correct to make sure the engineered epitopes can be recognized by cognate autoantibodies from patients. The other is the role of autoantibodies in the pathogenesis of a disease should be well investigated to make sure their pathogenicity (page 3, right column). Chen et al. teaches that regulatory T cells (Tregs) also play a critical role in regulating the immune system by inhibiting the function of immune cells to keep immunologic self-tolerance and immune homeostasis, and an AID will occur when the specific transcription factor Forkhead box protein P3 (Foxp3) of Tregs is mutated or the CD4+CD25+ T cells are eliminated. Therefore, applying Treg therapy in AIDs after being engineered to CAR-Tregs having antigen specificity may be a new choice (page 5, right column). Using CAR-T cells to treat AIDs, CARs can be tailored according to specific antigens or antibodies in different AIDs, so CAR-T cells have unique specificity (page 6, column 2). Nevertheless, finding the specific antigens to construct antigen specific CARs is not easy in some disease conditions (page 6, column 2). Chen et al. teaches that for the use of CAR-Tregs, attention should be paid to several issues. On the on hand, the immunosuppressive phenotype of Tregs will change after losing Foxp3 expression under an inflammatory microenvironment, from the immunosuppressive state to effector cells that aggravate disease symptoms (page 7, column 1).
Fransson et al (Journal of Neuroinflammation, 2012, 9:112) teaches CAR/FoxP3-engineered T regulatory cells (Treg) target the CNS and suppress experimental autoimmune encephalomyelitis (EAE) upon intranasal delivery (abstract), wherein the Treg cells are engineered to express a CAR targeting myelin oligodendrocyte glycoprotein (MOG).
As evidenced by Chen and Fransson, for CAR-T cells and CAR-NK cells to treat an autoimmune disease or infectious disease, CARs must be designed to recognize a specific antigen that is involved in the disease (a disease-relevant antigen). In the instant case, the specification does not identify any specific antigens that could be targeted by CAR T or CAR NK cells for treatment. The prior art does not supplement the missing information. The claims require the CAR T cell or CAR NK cell to have a function of being capable of treating a disease. However, neither the specification nor the prior art discloses the CAR specificity. The specification neither discloses a representative number of species for the genus, nor does it disclose a correlation between a structure of a CAR T cell or CAR NK cell and a function of being capable of treating an autoimmune disease or an infectious disease. Because one cannot envision the members of the genus of CAR T or CAR NK cells, one would not consider applicant was in possession of the claimed invention.
Conclusion
11. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/HONG SANG/Primary Examiner, Art Unit 1643
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