DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 30-33, 39 and 40-43 are pending.
Claims 2, 7, 16, 18, 20, 22, 25, 26, 30 are amended.
Claims 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 30-33, 39 and 40-43 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The priority application 63/119,234 claim 1 recites “….(ii) a ligand, which can be bound by a cell surface receptor on an immunosuppressive cell or a cell surface receptor on a cancerous cell…..” It does not however recite term “overexpression” for the ligand receptor as is recited in instant claim 1. In addition, the specification of the priority application 63/119,234 also do not disclose the term “overexpression” throughout the document. This term is however, recited in claim 1 of the PCT/US2021/061026 application. In addition, the limitations in claim 6 of “an inhibitor of Src homology 2 domain-containing tyrosine phosphatase 1 and 2 (SHP1/2), an inhibitor of T cell protein tyrosine phosphatase (TC-PTP), an inhibitor of diacylglycerol kinase (DGK), an inhibitor of enhancer of zeste homolog 2 (EZH2), and an inhibitor of transforming growth factor beta (TGFβ)” are also not recited or disclosed in the 63/119,234 priority application. As such, the U.S. effective filing date of all claims under examination is thus set at 11/29/2021 based on the 371 application PCT/US2021/061026 (filed 11/29/2021).
Information Disclosure Statement
The information disclosure statements (IDS) submitted are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 5, 6 and 7 are objected to because of the following informalities:
Claims 5, 6 and 7 are objective to because they appear to have a typographical errors where the word “the” is missing before the phrase “at least one SMDC” in each of the said claims. It is suggested that claim 5 be amended to recite “……wherein the drug moiety in the at least one SMDC is an agonist of……”, claim 6 be amended to recite “……wherein the drug moiety in the at least one SMDC is selected from……”, and claim 7 be amended to recite “……wherein the drug moiety in the at least one SMDC is an agonist of……”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 6, 22, 26, 30-33, 39 and 40-42 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.
Claim 6 recites the phrase “such as” in line 8. The metes-and-bounds of the claim are unclear because it is unclear how, or if, possible limitations following “such as” limit the claims.
Claim 22 recites “….the recognition region is a scFv region of an anti-FITC antibody….”. It is unclear how this further limits claim 2 which it depends upon and which recites “….wherein the CAR binds a cell-surface antigen on an immunosuppressive cell or a cancer cell with specificity” because FITC is not a cell-surface antigen on an immunosuppressive cell or a cancer cell.
Claims 26, 30, 31, 32, 33, 39, 40, 41 and 42 recite the phrase “… the patient…”. There is insufficient antecedent basis for “the patient” in the claims as claim 26 recites “a subject” in line 1. This rejection can be obviated by replacing “the patient” with “the subject”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1, 4, 7, 12, 20, 25, 26, 31-33, 39, 40 and 43 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Low et al. (WO2014100615A1 Date Published 2014-06-26) as evidenced by Yi (Immune Network 2016 Dec;16(6):337-343) and Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72).
Low et al. teaches a two-component cancer therapeutic comprising: (a) a small conjugate molecule (SCM) comprising a targeted moiety conjugated to a tumor receptor ligand, wherein the tumor receptor ligand is folate; and (b) chimeric antigen receptor (CAR)-expressing cytotoxic lymphocytes, wherein the CAR is a fusion protein comprising a recognition region, a co-stimulation domain and an activation signaling domain, and wherein the CAR has binding specificity for the targeted moiety (paragraph [0022]). As evidenced by Yi, the folate receptor (FR) is a cell surface glycosylphosphatidylinositol (GPI)-anchored glycoprotein with three isoforms, FR-α, FR-β, and FR-γ found in humans (Abstract). Yi also teaches that FRs are highly expressed on cancer cells and activated macrophages, whereas expression on normal cells is undetectable, indicating that FR-targeting could be a good selective strategy for the diagnosis and therapeutic treatment of cancers and activated macrophage-mediated diseases (Abstract). Therefore, the folate ligand that is taught by Low et al. is a ligand that is specific to the folate receptor (FR), that is overexpressed on macrophages, an immunosuppressive cell, and on cancer cells, thus anticipating the limitations of instant claim 1.
Low et al. also teaches that the targeted moiety of the SCM may be fluorescein isothiocyanate (FITC) (paragraph [0023]), and the recognition region of the CAR is a single chain fragment variable (scFv) region of an anti-FITC antibody (paragraph [0008]). According to instant claims 1 and 7, instant combination comprises a small molecule drug conjugate (SMDC) comprising a drug moiety conjugated to a ligand, wherein the drug moiety in the SMDC is FITC. Therefore, the SCM comprising FITC-folate as taught by Low et al. anticipates the instant SMDC.
Low et al. further teaches that cancer cell lines L1210A (murine leukemia cell line) and KB (human epidermoid carcinoma cell line) were first incubated with growth medium containing 70nM FITC-Folate conjugate or FITC-(PEG)12-Folate conjugate, followed by washing and subsequently incubated with CAR-expressing effector T cells at an amount of (effector T cells to target cancer cell) ratio of (20:1) (paragraphs [0112] and [00126]). They also teach that in the presence of the FITC-Folate conjugate, anti-FITC CAR-expressing T cells were redirected to FR+ cancer cells and caused specific cytolysis, and the activation of CAR-expressing T cells can be regulated by controlling the amount of FITC-Folate conjugates administered, whereas in the absence of FITC-Folate conjugates, CAR-expressing T cells showed negligible activity (paragraphs [0064], [00129] to [00131]). Therefore, Low et al. teaches that the combination comprising a first amount of (a) SCM and a second amount of (b) CAR-expressing lymphocytes, together are effective to effect cancer cell killing to treat cancer.
Low et al. also further teaches that the targeted moiety and the ligand are conjugated via a linker domain that can include polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, an unnatural peptideoglycan, polyvinylpyrrolidone, pluronic F-127, and (PEG)12 (paragraph [0018]). They teach that the targeted moiety is FITC and the linker is (PEG)12 (paragraph [0047]). They also teach that the co-stimulation domain of the CAR is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS), and that the activation signaling domain of the CAR is the T cell CD3ζ chain or Fc receptor γ (paragraphs [0010] and [0011]). They also teach that the cytotoxic lymphocytes are one or more of cytotoxic T cells, natural killer (NK) cells, and lymphokine-activated killer (LAK) cells (paragraph [0031]). They further teach that cancer cell lines L1210A and KB have higher folate receptor expression on their cell surfaces and that folate receptors are expressed on cells of cancers that include cancers of the ovary, cervix, endometrium, lung, kidney, brain, breast, colon, and head and neck cancers (paragraphs [0066] and [0112]). As evidenced by Yi, folate receptor α (FR-α) is overexpressed on cancer cells of the ovary, lung, breast, kidney, brain, endometrium, and colon (Pg. 337 and 338 paragraphs spanning). Further evidence is given by Siwowska et al. that teaches cervical KB tumor cells express folate receptor alpha (Abstract). KB cells were the cancer cells that were treated by the two-component cancer therapeutic of Low et al. (paragraphs [0112] and [00126]).
Moreover, Low et al. teaches a method of treating cancer in a subject, the method comprising: administering a therapeutically effective number of the CAR-expressing lymphocytes to a subject having cancer; and administering a small conjugate molecule (SCM) comprising a targeted moiety conjugated to a tumor receptor ligand to the subject, wherein the ligand is recognized and bound by a receptor on the surface of a cell of the cancer, and wherein the CAR has binding specificity for the targeted moiety; thereby treating cancer in a subject (paragraph [0034]). They teach that CAR-expressing lymphocytes comprised in a formulation can be administered to a subject having cancer via parenteral administration including subcutaneously, intramuscularly, intraperitoneally, intravenously (paragraph [0099]). They also teach that the formulation comprising SCM to be administered to the subject can be prepared in a formulation that is appropriate for the subject receiving the molecules, including having a volume of between about 1 ml and 50 ml and contain between about 20 ug/kg body weight and 3 mg/kg body weight SCM (paragraph [00101]). As such they teach formulations of SCM that are compatible for intravenous, intramuscular and subcutaneous administration in terms of volume and amount based on body weight. They further teach that the SCM may be administered prior to, simultaneous with, or after the CAR-expressing lymphocytes (paragraph [00102]).
Further, Low et al. teaches that the SCMs are prepared in a pharmaceutically acceptable formulation that may contain a pharmaceutically acceptable carrier or diluent formulation that can comprise about 50 µg/kg body weight SCM in a volume of about 10 ml (paragraphs [0070] and [00100]) Low et al. also teaches that CAR-expressing lymphocyte cells are resuspended and formulated in a pharmaceutically acceptable carrier or diluent that can comprise about 1 x 109 transduced cells in a volume of about 100 ml (paragraphs [0093] and [00100]). Therefore, Low et al. anticipates the combination cancer therapy of instant claim 43.
Taken together, the teachings of Low et al. described above anticipate instant claims 1, 4, 7, 12, 20, 25, 26, 31, 32, 33, 39, 40 and 43.
Claim Rejections - 35 USC § 103 (First)
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 2, 4, 7, 12, 18-20, 22, 25, 26, 31, 32, 33, 39, 40 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Low et al. (WO2014100615A1 Date Published 2014-06-26), as applied to claims 1, 4, 7, 12, 20, 25, 26, 31-33, 39, 40 and 43, and in further view of Yi (Immune Netw 2016 Dec;16(6):337-343) and Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72).
The combined teachings of Low et al., Yi and Siwowska et al. have been described in the 102 rejection above.
Low et al. does not specifically teach the combination cancer therapy of instant claim 1, wherein the CAR binds a cell-surface antigen on an immunosuppressive cell or a cancer cell with specificity, or wherein the recognition region is a single chain variable fragment (scFv) of an antibody that binds to a cell- surface antigen with high specificity, or wherein the cell-surface antigen is CD19. They also do not specifically teach combination cancer therapy of instant claim 2, wherein: the recognition region is a scFv region of an anti-FITC antibody, the co-stimulation domain is CD28, and the activation signaling domain is a T cell CD3ζ chain; the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD137 (4-1BB), and the activation signaling domain is a T cell CD3 ζ chain; or the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD28, and the activation signaling domain is a T cell CD3 ζ chain.
However, these deficiencies are made up in the teachings of Low et al.
Low et al. teaches that CD19 is a tumor-associated antigen that is expressed on malignant B cells and CARs containing anti-CD 19 antibody were able to achieve remission of malignant B cells when used to treat patients (paragraph [0004]). They teach the anti-FITC CAR (CAR4-1BBZ), which comprises an anti-FITC scFv, a CD8a hinge, a transmembrane domain ("TM"), the co-stimulation domain 4-1BB, and the activation signaling domain CD3ζ (paragraph [0085], Figure 1A and SEQ ID NO: 1).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating a subject for cancer in need thereof comprising administering a combination cancer therapy comprising a SMDC and CAR-expressing cytotoxic lymphocytes by substituting the scFv domain of the anti-FITC CAR (CAR4-1BBZ comprising anti-FITC scFv, 4-1BB co-stimulation domain and CD3ζ activation signaling domain) as taught by Low et al. with the scFv domain of CD19 also as taught by Low et al. (paragraph [0004]) to arrive at a CAR that binds CD19, which is a cell-surface tumor associated antigen expressed on malignant B cells also as taught by Low et al. (paragraph [0004]), because Low et al. teaches that patients treated with anti-CD 19 CAR experienced remission of disease (paragraph [0004]). One can further substitute the co-stimulation domain of 4-1BB with the co-stimulation domain of CD28 also as taught by Low et al. (paragraph [0029]) with a reasonable expectation of success that such a construct will produce functional anti-CD19 CAR-expressing cytotoxic lymphocytes. Alternatively, by substituting the co-stimulation domain 4-1BB of the anti-FITC CAR (CAR4-1BBZ) as taught by Low et al. with the co-stimulation domain of CD28, also as taught by Low et al. (paragraph [0010]) to produce functional anti-FITC CAR-expressing cytotoxic lymphocytes because Low et al. teaches that the co-stimulation domains 4-1BB (CD137), CD28 or CD134 have been included in second generation CARs to achieve prolonged activation of T cells (paragraph [0003]). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (second)
Claim(s) 1, 2, 4, 7, 12, 13, 18-20, 22, 25, 26, 31-33, 39, 40 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Low et al. (WO2014100615A1 Date Published 2014-06-26), Yi (Immune Netw 2016 Dec;16(6):337-343) and Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72) as applied to claims 1, 2, 4, 7, 12, 18-20, 22, 25, 26, 31-33, 39, 40 and 43 above and further in view of Hermanson (Bioconjugate Techniques (Third Edition), Academic Press, 2013, Pages 465-505 Chapter 11).
The combined teachings of Low et al., Yi and Siwowska et al. render obvious instant claims 1, 2, 4, 7, 12, 18-20, 22, 25, 26, 31-33, 39, 40 and 43 as discussed above in the first 103 rejection.
They do not specifically teach the combination cancer therapy of claim 4, wherein the linker is (PEG)3. However, these deficiencies are made up in the teachings of Hermanson.
Hermanson teaches conjugates Psoralen–PEG3–Biotin, a photoreactive biotinylation reagent containing a psoralen group at one end and a triethylene glycol (PEG-based) spacer in the middle which is water soluble due to the presence of the hydrophilic PEG arm and has been used to label double-stranded DNA for detection using (strept)avidin reagents (Pg. 498 column left paragraph second). Hermanson also teaches the conjugate Biotin–PEG3–Phosphine, a reagent that has a biotin handle at one end, a triethyleneglycol (PEG) diamine spacer imparting increased water solubility in the middle, and a 3-(diphenylphosphino)-4-(methoxycarbonyl)benzamide group on the other end that can be used to specifically label glycans or proteins in living organisms because of the lack of toxic side reactions or additives (Pg. 504 column right paragraph second and Pg. 505 column left paragraph second).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating a subject for cancer in need thereof comprising administering a combination cancer therapy comprising a SMDC and CAR-expressing cytotoxic lymphocytes by substituting the (PEG)12 linker taught by Low et al. with the PEG3 linker taught by Hermanson as the linker for the FITC-Folate SMDC because Hermanson teaches that small molecule conjugates that comprises PEG3 linkers have increased water solubility and such conjugates have been successfully used for biological labelling without causing toxicity to the organisms (Pg. 498 column left paragraph second, Pg. 504 column right paragraph second and Pg. 505 column left paragraph second). This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (third)
Claim(s) 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 31-33 and 39-43 are rejected under 35 U.S.C. 103 as being unpatentable over Low et al. (WO2014100615A1 Date Published 2014-06-26), Yi (Immune Netw 2016 Dec;16(6):337-343), Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72) and Hermanson (Bioconjugate Techniques (Third Edition), Academic Press, 2013, Pages 465-505 Chapter 11) as applied to claims 1, 2, 4, 7, 12, 13, 18-20, 22, 25, 26, 31-33, 39, 40 and 43 above and further in view of Low (2) et al. (US20190216935A1 Date Published 2019-07-18) and Chi et al. (Frontiers in Pharmacology, 31 May 2017, Vol. 8, No. 304, Pgs. 1-10; presented in the ISR dated 03/21/2022).
The combined teachings of Low et al., Yi, Siwowska et al. and Hermanson render obvious instant claims 1, 2, 4, 7, 12, 13, 18-20, 22, 25, 26, 31-33, 39, 40 and 43 as discussed above in the second 103 rejection.
They do not specifically teach the combination cancer therapy of claim 1, wherein the drug moiety in the at least one SMDC is an agonist of a pattern recognition receptor located in the endosome or the cytoplasm of a cell, or wherein the drug moiety in the at least one SMDC is an agonist of a toll-like receptor (TLR), or wherein the SMDC is a folate-TLR7 agonist, a releasable form of a folate-(PEG)3-TLR7 agonist, or a non-releasable form of a folate-(PEG)3-TLR7 agonist.
They also do not specifically teach the method of claim 26, wherein administering the combination cancer therapy increases an amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to an amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME, or wherein administering the combination cancer therapy reduces an amount of myeloid-derived suppressor cells present within a TME of the subject.
However, these deficiencies are made up in the teachings of Low (2) et al. and Chi et al.
Low (2) et al. teaches methods for treating a cancer using compounds comprising a folate receptor binding ligand attached to a drug via a linker (Abstract). They teach a method for treating a folate receptor-negative (FR-) cancer or a folate receptor-positive (FR+) cancer comprising administering to the host a therapeutically effective amount of one or more compounds comprising a folate receptor binding ligand attached to a drug via a linker to inhibit or deplete myeloid-derived suppressor cells (MDSCs), and as such treating the cancer having the MDSCs (paragraphs [0015], [0017], [0018] and [0022]), wherein the folate receptor binding ligand is specific for folate receptor β and wherein the folate receptor binding ligand binds to the folate receptor β on the myeloid-derived suppressor cells (paragraph [0022]).
Low (2) et al. also teaches that “myeloid-derived suppressor cells” (MDSCs) refer to cells that exist in the microenvironment of a cancer or a tumor, also known as the tumor microenvironment (TME) as recited in instant claims 41 and 42, and that MDSCs are immunosuppressive (paragraphs [0099] and [0100]). They also teach that the drug is a TLR7 agonist which reprograms MDSCs (paragraphs [0031] to [0033]). They teach the synthesis of folic acid conjugates of TLR7 agonist (paragraph [0254 and Scheme 5). They also teach that when treated with the conjugate of FA-TLR7 agonist, the cell population of FR+ TAMs/MDSCs in 4T1 solid tumor dramatically decreased compared with untreated control (paragraph [0208] and FIG. 24; TAMs is abbreviation for tumor associated macrophages).
Low (2) et al. also teaches that the targeting of MDSCs to deplete or to inhibit the activity of MDSCs can result in inhibition of tumor growth, complete or partial elimination of a tumor, stable disease and killing of tumor cells (paragraph [0158]). They teach that to “deplete” or “inhibit” MDSCs means to kill some or all of a population of MDSCs, to inhibit or eliminate the activity of MDSCs (e.g., reducing or eliminating the ability of MDSCs to stimulate angiogenesis in tumor tissue), to reprogram MDSCs so that MDSCs inhibit rather than support tumor survival, to prevent an increase in numbers of MDSCs or reduce the number of MDSCs, or to have any other effects on MDSCs that results in an anti-cancer therapeutic effect for the host (paragraph [0158]). They also teach that the ratio of M1 to M2 macrophages in 4T1 solid tumor TME after FA-TLR7 agonist treatment were compared with those from untreated control, which showed that the targeting of FR+ TAMs/MDSCs in 4T1 solid tumor resulted in converting the immunosuppressive M2 macrophages environment to an anti-cancer M1 macrophages environment, which would contribute to the slow growth of a tumor (paragraph [0219] and FIG. 25). Therefore, they teach that treatment of solid tumor with FA-TLR7 agonist conjugate converted macrophages, which are a type of myeloid cells, into an immune-stimulating phenotype. They further teach that mice carrying 4T1 solid tumor treated with FA-TLR7 agonist conjugate to target MDSCs/TAMs showed slowing of tumor growth and experienced significantly increased survival after elimination of the immunosuppression function of MDSCs/TAMs (paragraphs [0229], [0243], FIG. 21, FIG. 22, FIG. 36 and FIG. 37).
As confirmed by Chi et al., toll like receptors (TLRs) are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity and TLR7, a member of the TLR family, is an intracellular receptor expressed on the membrane of endosomes (Abstract). Chi et al. also teaches that TLR7 agonists are frequently applied in preclinical and clinical investigations due to their anti-tumor activity (Abstract). Therefore, the TLR7 agonist taught by Low (2) et al. is an agonist of a pattern recognition receptor located in the endosomes of a cell.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating a subject for cancer in need thereof comprising administering a combination cancer therapy comprising a SMDC and CAR-expressing cytotoxic lymphocytes by substituting the drug/targeted moiety that is FITC in the FITC-folate SMDC conjugate as taught by Low et al. with the drug moiety of TLR7 agonist as taught by Low (2) et al. because Low (2) et al. teaches that the conjugate of FA-TLR7 agonist dramatically reduced the cell population of FR+ TAMs/MDSCs in 4T1 solid tumor (paragraph [0208] and FIG. 24) and that reducing immunosuppressive MDSCs in the TME can result in the inhibition of tumor growth, or the complete or partial elimination of a tumor (paragraph [0158]). This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to claims 41 and 42, since Low (2) et al. teaches that the effect of FA-TLR7 agonist is to dramatically decrease the population of TAMs/MDSCs in 4T1 solid tumor (paragraph [0206]), and the targeting of FR+ TAMs/MDSCs in 4T1 solid tumor with FA-TLR7 agonist treatment resulted in converting the immunosuppressive M2 macrophages environment to an anti-cancer M1 macrophages environment (paragraph [0219]), it would be reasonable to expect that the combination of a folate-TLR7 agonist(SMDC) and a CAR-expressing cytotoxic lymphocyte, would also increase the amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to the amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME, or reduce the amount of myeloid-derived suppressor cells (MSDCs) present within a TME of the subject.
Claim Rejections - 35 USC § 103 (fourth)
Claim(s) 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 30-33 and 39-43 are rejected under 35 U.S.C. 103 as being unpatentable over Low et al. (WO2014100615A1 Date Published 2014-06-26), Yi (Immune Netw 2016 Dec;16(6):337-343), Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72), Hermanson (Bioconjugate Techniques (Third Edition), Academic Press, 2013, Pages 465-505 Chapter 11), Low (2) et al. (US20190216935A1 Date Published 2019-07-18) and Chi et al. (Frontiers in Pharmacology, 31 May 2017, Vol. 8, No. 304, Pgs. 1-10; presented in the ISR dated 03/21/2022) as applied to claims 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 31-33 and 39-43 above and further in view of Minn et al. (The Lancet Oncology, Volume 20, Issue 8, e443 - e451, 2019).
The combined teachings of Low et al., Yi, Siwowska et al., Hermanson, Low (2) et al. and Chi et al. render obvious instant claims 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 31-33 and 39-43 as discussed above in the third 103 rejection.
They do not specifically teach he method of instant claim 26, wherein the cancer is a solid tumor cancer and further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy. However, these deficiencies are made up in the teachings of Minn et al.
Minn et al teaches short-term strategies to improve CAR T-cell therapy responses, particularly for solid tumors (Summary). They teach combining CAR T-cell therapy with careful monitoring and non-invasive imaging (Summary). They also teach that by utilizing imaging, greater mechanistic insights into the cascade of events within the tumor can be gained to enable tumor eradication by CAR T-cell therapy (Summary).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating a subject for cancer in need thereof comprising administering a combination cancer therapy comprising a SMDC and CAR-expressing cytotoxic lymphocytes that further comprises imaging the solid tumor cancer prior to or during administering the combination cancer therapy because Minn et al. teaches that combining CAR T cell therapy with imaging of solid tumors can enable improved tumor eradication of the CAR T-cell therapy (Summary). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Double Patenting
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.
First NSDP Application No. 18/260273
Claims 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 30-33, 39 and 40-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 15, 16, 18-23, 25, 31, 37-41 of copending Application No. 18/260273 in view of Low et al. (WO2014100615A1 Date Published 2014-06-26), Yi (Immune Netw 2016 Dec;16(6):337-343), Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72), Hermanson (Bioconjugate Techniques (Third Edition), Academic Press, 2013, Pages 465-505 Chapter 11) and Minn et al. (The Lancet Oncology, Volume 20, Issue 8, e443 - e451, 2019).
Both the copending claims and the instant claims are drawn to a method of treating a cancer subject comprising administering a first therapy comprising a folate ligand attached to a TLR agonist via a linker and a second therapy comprising a CAR T-cell. However, the copending claims do not specifically recite a PEG3 linker, or a CAR comprising a CD19 scFv, a co-stimulation domain and/or activation signaling domain as recited in instant claim 22, or the combination therapy further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy, or the cancer is a folate receptor expressing cancer, or the combination therapy reduces an amount of myeloid-derived suppressor cells present within a TME of the subject, or the pharmaceutical composition of instant claim 43. These deficiencies are made-up in the teachings of Low et al., Yi, Siwowska et al., Hermanson and Minn et al.
The teachings of Low et al., Yi, Siwowska et al., Hermanson, and Minn et al. are discussed above.
It would be obvious to perform a combined method to generate and administer the products of the copending claims for a method of treating a subject for cancer wherein the linker of the SMDC comprises a PEG3 linker as taught by Hermanson because said linker is non-toxic and is a suitable small molecule conjugate linker, or the CAR comprises a CD19 scFv, a co-stimulation domain and an activation signaling domain as taught by Low et al. because it is capable of killing malignant B cells to achieve remission, or the method of treating a solid cancer with the combination therapy further comprising imaging prior to or during administering the combination cancer therapy as taught by Minn et al. because said imaging can guide CAR T-cell therapy to further enhance its efficacy to eradicate tumor cells.
This is a provisional nonstatutory double patenting rejection.
Second NSDP Application No. 18/869,271
Claims 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 30-33, 39 and 40-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 46, 51, 53, 57-60, 62, 70, 71 and 102 of copending Application No. 18/869,271 in view of Low et al. (WO2014100615A1 Date Published 2014-06-26), Chi et al. (Frontiers in Pharmacology, 31 May 2017, Vol. 8, No. 304, Pgs. 1-10; presented in the ISR dated 03/21/2022), Hermanson (Bioconjugate Techniques (Third Edition), Academic Press, 2013, Pages 465-505 Chapter 11) and Minn et al. (The Lancet Oncology, Volume 20, Issue 8, e443 - e451, 2019).
Both the copending claims and the instant claims are drawn to a method of treating a cancer subject comprising administering a first therapy comprising a folate ligand attached to a drug moiety via a linker and a second therapy comprising a CAR T-cell. However, the copending claims do not specifically recite wherein the drug moiety in at least one SMDC is an agonist of a pattern recognition receptor located in the endosome or the cytoplasm of a cell, or wherein the drug moiety in at least one SMDC is an agonist of TLR, or fluorescein isothiocyanate (FITC), or wherein the linker is a PEG3 linker, or wherein the SMDC is a folate-TLR7 agonist, or wherein the cancer is a solid tumor cancer and further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy, or wherein one or both of the at least one SMDC and the CAR-expressing cytotoxic lymphocytes is administered to the subject via a mode of administration selected from the group consisting of intravenously, intramuscularly, intraperitoneally, and subcutaneously, or wherein a mode of administration of the at least one SMDC is independent of a mode of administration of the CAR-expressing cytotoxic lymphocytes, or wherein the first therapeutically effective amount of the at least one SMDC and the second therapeutically effective amount of the CAR-expressing cytotoxic lymphocytes are administered simultaneously or sequentially, in either order, or wherein administering the combination cancer therapy increases an amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to an amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME, or wherein administering the combination cancer therapy reduces an amount of myeloid-derived suppressor cells present within a TME of the subject. These deficiencies are made-up in the teachings of Low et al., Low (2) et al., Chi et al., Hermanson and Minn et al.
The teachings of Low et al., Low (2) et al., Chi et al., Hermanson and Minn et al. are discussed above.
It would be obvious to perform a combined method to generate and administer the products of the copending claims for a method of treating a subject for cancer wherein the drug moiety of the SMDC is FITC as taught by Low et al. because Low et al. teaches FITC-Folate-conjugates are able to redirect anti-FITC CAR-T cells to FR+ cancer cells; or wherein the drug moiety is an agonist of a pattern recognition receptor located in the endosome or the cytoplasm of a cell as taught by Chi et al., or wherein the SMDC is a folate-TLR7 agonist as taught by Low (2) et al. and Chi et al, or wherein administering the combination cancer therapy increases an amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to an amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME as taught by Low (2) et al. and Chi et al., or wherein administering the combination cancer therapy reduces an amount of myeloid-derived suppressor cells present within a TME of the subject as taught by Low (2) et al. and Chi et al. because Low (2) et al. teaches a method of administering FA-TLR7 agonist conjugate for the treatment of solid tumor where the conjugate decreased the number of TME MDSCs and converted TME macrophages into immune-stimulating phenotype; or wherein the linker is a PEG3 linker as taught by Hermanson because Hermanson teaches said linkers are safe and non-toxic; or the method of treating a solid cancer with the combination therapy further comprising imaging prior to or during administering the combination cancer therapy as taught by Minn et al. because said imaging can guide CAR T-cell therapy to further enhance its efficacy to eradicate tumor cells; or wherein one or both of the at least one SMDC and the CAR-expressing cytotoxic lymphocytes is administered to the subject via a mode of administration selected from the group consisting of intravenously, intramuscularly, intraperitoneally, and subcutaneously as taught by Low et al., or wherein a mode of administration of the at least one SMDC is independent of a mode of administration of the CAR-expressing cytotoxic lymphocytes as taught by Low et al., or wherein the first therapeutically effective amount of the at least one SMDC and the second therapeutically effective amount of the CAR-expressing cytotoxic lymphocytes are administered simultaneously or sequentially, in either order as taught by Low et al. because Low et al. teaches administration of SCM and CARs in said manner for a two component cancer therapeutic in the treatment of cancer.
This is a provisional nonstatutory double patenting rejection.
Third, fourth and fifth NSDP Application Nos. 18/823,426, 16/302,912 and 19/264,776
Claims 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 30-33, 39 and 40-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1, 3, 4 and 7-12 of copending Application No. 18/823,426;
claims 1, 9, 12, 50, 52, 53 and 54 of copending Application No. 16/302,912; and
claims 27-29, 31-33 and 35-39 of copending Application No. 19/264,776,
in view of Low et al. (WO2014100615A1 Date Published 2014-06-26), Yi (Immune Netw 2016 Dec;16(6):337-343), Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72), Low (2) et al. (US20190216935A1 Date Published 2019-07-18), Hermanson (Bioconjugate Techniques (Third Edition), Academic Press, 2013, Pages 465-505 Chapter 11) and Minn et al. (The Lancet Oncology, Volume 20, Issue 8, e443 - e451, 2019).
All three copending claims and the instant claims are drawn to a method of treating a cancer comprising administering to the host a therapeutically effective amount of one or more compounds comprising a folate receptor binding compound or ligand attached to a drug via a linker, wherein the drug is a TLR7 agonist.
Copending 18/823,426 claims are also drawn to targeting tumor-associated macrophages, wherein said compound binds to tumor-associated macrophages and said TLR agonist reprograms tumor associated macrophages from an M2 to an M1 phenotype.
Copending 16/302,912 claims are also drawn to targeting myeloid-derived suppressor cells (MDSCs) and said TLR7 agonist reprograms myeloid- derived suppressor cells from an M2 to an M1 phenotype.
However, the copending claims do not specifically recite a method of treating a subject for cancer in need thereof comprising administering a combination cancer therapy comprising a first amount of one or more folate receptor binding compound attached to a drug via a linker, in combination with a second amount of CAR-expressing cytotoxic lymphocytes, which together are effective to treat cancer. The copending claims also do not specifically recite a combination cancer therapy wherein the CAR is a fusion protein comprising a recognition region, a co-stimulation domain, and an activation signaling domain, and wherein the CAR binds a cell-surface antigen on an immunosuppressive cell or a cancer cell with specificity, or the recognition region is a single chain variable fragment (scFv) of an antibody that binds to a cell-surface antigen with high specificity, or wherein the cell-surface antigen is CD 19, or wherein the co-stimulation domain is CD28 or CD137 (4-1BB); and/or the activation signaling domain is a T cell CD3 chain or a Fc receptor ϒ, or wherein: the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD137 (4-1BB), and the activation signaling domain is a T cell CD3ζ chain; or the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD28, and the activation signaling domain is a T cell CD3 ζ chain. They further do not specifically recite wherein the cytotoxic lymphocytes are cytotoxic T cells or natural killer (NK) cells, or a combination of two or more of the foregoing.
They do not specifically recite wherein the cancer is a folate receptor α- or β-expressing cancer. They also do not specifically recite wherein administering the combination cancer therapy further comprises administering a first therapeutically effective amount of the at least one SMDC and a second therapeutically effective amount of the CAR-expressing cytotoxic lymphocytes, or wherein the first therapeutically effective amount of the at least one SMDC and the second therapeutically effective amount of the CAR- expressing cytotoxic lymphocytes are administered simultaneously or sequentially, in either order. They further do not specifically recite the combination cancer therapy for treating a subject for cancer, wherein one or both of the at least one SMDC and the CAR-expressing cytotoxic lymphocytes is administered to the subject via a mode of administration selected from the group consisting of intravenously, intramuscularly, intraperitoneally, and subcutaneously, wherein a mode of administration of the at least one SMDC is independent of a mode of administration of the CAR-expressing cytotoxic lymphocytes, or wherein administering the combination cancer therapy increases an amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to an amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME, or wherein administering the combination cancer therapy reduces an amount of myeloid-derived suppressor cells present within a TME of the subject. They also further do not specifically recite a combination cancer therapy comprising: a first pharmaceutical composition comprising at least one SMDC comprising a drug moiety or pharmaceutically acceptable salt thereof conjugated to a ligand, wherein the ligand is specific to a receptor overexpressed on an immunosuppressive cell or a cancer cell; and a second pharmaceutical composition comprising CAR-expressing cytotoxic lymphocytes; wherein the combination comprises a first amount of the first pharmaceutical composition and a second amount of the second pharmaceutical composition.
They also do not specifically recite a combination wherein the linker comprises a PEG or the linker is a (PEG)3, or wherein the cancer is a solid tumor cancer and further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy.
However, these deficiencies are made up in the teachings of Low et al., Yi, Siwowska et al., Low (2) et al., Hermanson and Minn et al.
It would be obvious to perform a combined method to generate and administer the products of the copending claims for a method of treating a subject for cancer in combination with CAR-expressing cytotoxic lymphocytes as taught by Low et al., wherein the CAR comprises a recognition region that is a scFv region of an anti-CD19 antibody, a co-simulation domain that is CD28 or CD137 (4-1BB), and an activation signaling domain that is a T cell CD3ζ chain, and wherein the CAR binds a cell-surface antigen on an immunosuppressive cell or a cancer cell with specificity such as CD19, and the administration mode and sequence also as taught by Low et al. because Low et al. teaches a combination therapy comprising a small molecule folate-drug conjugate and CAR-expressing lymphocytes with said characteristics together can be an effective method for the treatment of cancer that is a folate receptor α- or β-expressing cancer; or wherein administering the combination cancer therapy increases an amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to an amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME as taught by Low (2) et al., or wherein administering the combination cancer therapy reduces an amount of myeloid-derived suppressor cells present within a TME of the subject as taught by Low (2) et al. because Low (2) et al. teaches a method of administering FA-TLR7 agonist conjugate for the treatment of solid tumor where the conjugate decreased the number of TME MDSCs and converted TME macrophages into immune-stimulating phenotype; or wherein the linker attaching the folate receptor binding compound to the TLR7 agonist drug is (PEG)3 as taught by Hermanson because Hermanson teaches said linker is safe and non-toxic; or wherein the cancer is a solid tumor cancer and further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy as taught by Minn et al. because Minn et al. teaches that said imaging can guide CAR-T cell therapy.
This is a provisional nonstatutory double patenting rejection.
Sixth, Seventh and Eighth NSDP U.S. Patent Nos. US 8546425 B2, US 10363250 B2 and US 11219622 B2
Claims 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 30-33, 39 and 40-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-4 and 9-10 of U.S. Patent No. US 8546425 B2;
claims 1, 5, 8 and 9 of U.S. Patent No. US 10363250 B2; and
claims 1, 7, 9, 12-14 of U.S. Patent No. US 11219622 B2,
in view of Low et al. (WO2014100615A1 Date Published 2014-06-26), Yi (Immune Netw 2016 Dec;16(6):337-343), Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72), Low (2) et al. (US20190216935A1 Date Published 2019-07-18), Hermanson (Bioconjugate Techniques (Third Edition), Academic Press, 2013, Pages 465-505 Chapter 11) and Minn et al. (The Lancet Oncology, Volume 20, Issue 8, e443 - e451, 2019).
Although the claims at issue are not identical, they are not patentably distinct from each other because all three patented claims and the instant claims are drawn to a method of treating a population of cancer cells in a patient comprising administering a therapeutically effective amount of a conjugate comprising a folate receptor binding ligand attached to a drug via a linker. Of note, the specifications of the patents disclose that the antifolates recited in the patent claims are agents that are folate receptor binding (Column 2 lines 22-23 of US 8546425 B2; Column 2 lines 29-30 of US 10363250 B2; and Column 2 lines 30-31 of US 11219622 B2).
However, the copending claims do not specifically recite a method of treating a subject for cancer in need thereof comprising administering a combination cancer therapy comprising a first amount of one or more folate receptor binding compound attached to a drug via a linker, wherein the drug is an agonist of a pattern recognition receptor located in the endosome or the cytoplasm of a cell that is an agonist of a toll-like receptor (TLR) that is a TLR7 agonist; and in combination with a second amount of CAR-expressing cytotoxic lymphocytes, which together are effective to treat cancer. The copending claims also do not specifically recite a combination cancer therapy wherein the CAR is a fusion protein comprising a recognition region, a co-stimulation domain, and an activation signaling domain, and wherein the CAR binds a cell-surface antigen on an immunosuppressive cell or a cancer cell with specificity, or the recognition region is a single chain variable fragment (scFv) of an antibody that binds to a cell-surface antigen with high specificity, or wherein the cell-surface antigen is CD 19, or wherein the co-stimulation domain is CD28 or CD137 (4-1BB); and/or the activation signaling domain is a T cell CD3 chain or a Fc receptor ϒ, or wherein: the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD137 (4-1BB), and the activation signaling domain is a T cell CD3ζ chain; or the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD28, and the activation signaling domain is a T cell CD3 ζ chain. They further do not specifically recite wherein the cytotoxic lymphocytes are cytotoxic T cells or natural killer (NK) cells, or a combination of two or more of the foregoing.
They do not specifically recite wherein the cancer is a folate receptor α- or β-expressing cancer. They also do not specifically recite wherein administering the combination cancer therapy further comprises administering a first therapeutically effective amount of the at least one SMDC and a second therapeutically effective amount of the CAR-expressing cytotoxic lymphocytes, or wherein the first therapeutically effective amount of the at least one SMDC and the second therapeutically effective amount of the CAR- expressing cytotoxic lymphocytes are administered simultaneously or sequentially, in either order. They further do not specifically recite the combination cancer therapy for treating a subject for cancer, wherein one or both of the at least one SMDC and the CAR-expressing cytotoxic lymphocytes is administered to the subject via a mode of administration selected from the group consisting of intravenously, intramuscularly, intraperitoneally, and subcutaneously, wherein a mode of administration of the at least one SMDC is independent of a mode of administration of the CAR-expressing cytotoxic lymphocytes, or wherein administering the combination cancer therapy increases an amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to an amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME, or wherein administering the combination cancer therapy reduces an amount of myeloid-derived suppressor cells present within a TME of the subject. They also further do not specifically recite a combination cancer therapy comprising: a first pharmaceutical composition comprising at least one SMDC comprising a drug moiety or pharmaceutically acceptable salt thereof conjugated to a ligand, wherein the ligand is specific to a receptor overexpressed on an immunosuppressive cell or a cancer cell; and a second pharmaceutical composition comprising CAR-expressing cytotoxic lymphocytes; wherein the combination comprises a first amount of the first pharmaceutical composition and a second amount of the second pharmaceutical composition.
They also do not specifically recite a combination wherein the linker comprises a PEG or the linker is a (PEG)3, or wherein the cancer is a solid tumor cancer and further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy.
However, these deficiencies are made up in the teachings of Low et al., Yi, Siwowska et al., Low (2) et al., Chi et al., Hermanson and Minn et al.
It would be obvious to perform a combined method to generate and administer the products of the copending claims for a method of treating a subject for cancer comprising an antifolate that is a folate receptor binding ligand linked via a linker to a drug, wherein the drug is a TLR7 agonist as taught by Low (2) et al. and Chi et al., and in combination with CAR-expressing cytotoxic lymphocytes as taught by Low et al., wherein the CAR comprises a recognition region that is a scFv region of an anti-CD19 antibody, a co-simulation domain that is CD28 or CD137 (4-1BB), and an activation signaling domain that is a T cell CD3ζ chain, and wherein the CAR binds a cell-surface antigen on an immunosuppressive cell or a cancer cell with specificity such as CD19, and the administration mode and sequence also as taught by Low et al. because Low et al. teaches a combination therapy comprising a small molecule folate-drug conjugate and CAR-expressing lymphocytes with said characteristics together can be an effective method for the treatment of cancer that is a folate receptor α- or β-expressing cancer and Low (2) et al. teaches that solid tumors treated with FA-TLR7 agonist conjugate that can target MDSCs/TAMs showed slowing of tumor growth and experienced significantly increased survival; or wherein administering the combination cancer therapy increases an amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to an amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME as taught by Low (2) et al., or wherein administering the combination cancer therapy reduces an amount of myeloid-derived suppressor cells present within a TME of the subject as taught by Low (2) et al. because Low (2) et al. teaches a method of administering FA-TLR7 agonist conjugate for the treatment of solid tumor where the conjugate decreased the number of TME MDSCs and converted TME macrophages into immune-stimulating phenotype; or wherein the linker attaching the folate receptor binding compound to the TLR7 agonist drug is (PEG)3 as taught by Hermanson because Hermanson teaches said linker is safe and non-toxic; or wherein the cancer is a solid tumor cancer and further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy as taught by Minn et al. because Minn et al. teaches that said imaging can guide CAR-T cell therapy.
Ninth, Tenth, Eleventh, Twelfth and Thirteenth NSDP U.S. Patent Nos. US 12150981 B2, US 11850262 B2, US 11759480 B2, US 11779602 and B2 US 12240870 B2
Claims 1, 2, 4, 7, 12, 20, 22, 25, 26, 31-33, 40 and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-5, 16-20 and 31 of U.S. Patent No. US 12150981 B2;
claims 1, 3-7, 9, 12, 14-16 of U.S. Patent No. US 11850262 B2; and
claims 1 to 4 of U.S. Patent No. US 11759480 B2;
and claims 1, 2, 4, 7, 12, 20, 22, 25, 26, 31-33, 39, 40 and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-11, 18-44 of U.S. Patent No.US 11779602 B2,
claims 1-10 of U.S. Patent No.US 12240870 B2
Although the claims at issue are not identical, they are not patentably distinct from each other because all patented claims are drawn to a method of killing cancer cells or treating a patient for cancer comprising administering (i) an amount of a conjugate comprising a folate linked to fluorescein isothiocyanate (FITC) by a linker; and (ii) a CAR T cell composition comprising CAR T cells that specifically binds FITC.
In addition, patent specifications disclose the following:
US 12150981 B2 Patent specification discloses:
cytotoxic lymphocytes as one or more of cytotoxic T cells, natural killer (NK) cells, and lymphokine-activated killer (LAK) cells (Column 2 lines 62-65);
co-stimulation domain of the CAR is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS) (Column 2 lines 55-58);
activation signaling domain of the CAR is the T cell CD3ζ chain or Fc receptor γ (Column 2 lines 59-61);
the SCM can be administered prior to, simultaneous with, or after the CAR-expressing lymphocyte formulation (Column 16 lines 53-55).
US 11850262 Patent specification discloses:
cytotoxic T lymphocytes can be genetically engineered to express CAR constructs (Column 110 lines 42-44);
the method of treatment of a cancer comprises a cancer that is folate receptor expressing (Column 10 lines 9-10).
US 11759480B2 Patent specification discloses:
a method of treatment of a cancer comprising a small molecule ligand linked to a targeting moiety by a linker wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, an unnatural peptidoglycan, a polyvinylpyrrolidone, pluronic F-127, or a combination thereof (Column 7 lines 33-38 and Column 8 lines 32-38);
cytotoxic T lymphocytes can be genetically engineered to express CAR constructs (Column 111 lines 61-63);
a method of treating cancer comprising administering a dose of a small molecule ligand linked to a moiety by a linker and a CAR T cell composition comprising CAR directed to the moiety (Column 27 lines 13-29);
a method of treating cancer comprising administering a dose of a small molecule ligand linked to a moiety by a linker and a CAR T cell composition comprising CAR directed to the moiety (Column 27 lines 13-29);
a method of treating cancer wherein administration is by intravenous administration (Column 23 lines 13-29);
a method of treating cancer wherein administration of CAR T cells is followed by administration of fluorescein-folate (small molecule conjugate) (Column 179 lines 4-6).
US 11779602 B2 Patent specification discloses:
In FIG. 1, the construct of CAR that contains the following domains:
antiFL(FITC-E2)scFv-IgG4 hinge (CH2 (L235D, N297Q)-CH3)-CD28 TM-4-1BB-CD3z-T2A-EGFRt;
antiFL(FITC-4M5.3)scFv-IgG4 hinge (CH2 (L235D, N297Q)-CH3)-CD28 TM-4-1BB-CD3z-T2A-EGFRt;
In clause 127, the method wherein the cancer is a folate receptor expressing cancer (column 35 lines 62-63);
the terms “administer,” administering,” or “administered” mean all means of introducing the compound, or CAR T cell composition comprising CAR T cells that comprises an E2 anti-fluorescein antibody fragment, to the patient, including, but not limited to intravenous, intramuscular and subcutaneous (Column 22 lines 19-26);
the cancer is a folate receptor α-expressing cancer or a folate receptor β-expressing cancer (Column 39 lines 6-8).
US 12240870 B2 Patent specification discloses:
in clause 60, the method wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, an unnatural peptidoglycan, a polyvinylpyrrolidone, pluronic F-127, or a combination thereof;
cytotoxic T cells can be genetically engineered to express CAR constructs by transfecting a population of the T lymphocytes with an expression vector encoding the CAR construct (Column 50 lines 6-9);
In clause 69, the method wherein the cancer is a folate receptor expressing cancer;
the cancer is a folate receptor α-expressing cancer. In yet another embodiment, the cancer is a folate receptor β-expressing cancer;
the term “administering” or “administered” includes all means of introducing the compound, or pharmaceutically acceptable salt thereof, or CAR T cell composition to the patient, including intravenous, intramuscular and subcutaneous (Column 15 lines 29-34);
in clause 71, the method wherein the CAR has a recognition region and the recognition region is a single chain fragment variable (scFv) region of an antibody;
in clause 73, the method wherein the CAR has a co-stimulation domain and the co-stimulation domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS).
Fourteenth, Fifteenth, Sixteenth, Seventeenth and Eighteenth NSDP U.S. Patent Nos. US 12150981 B2, US 11850262 B2, US 11759480 B2, US 11779602 B2 and US 12240870 B2
Claims 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 30-33, 39 and 40-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-5, 16-20 and 31 of U.S. Patent No. US 12150981 B2;
claims 1, 3-7, 9, 12, 14-16 of U.S. Patent No. US 11850262 B2;
claims 1 to 4 of U.S. Patent No. US 11759480 B2;
claims 1-11, 18-44 of U.S. Patent No.US 11779602 B2; and
claims 1-10 of U.S. Patent No.US 12240870 B2
in view of Low et al. (WO2014100615A1 Date Published 2014-06-26), Yi (Immune Netw 2016 Dec;16(6):337-343), Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72), Low (2) et al. (US20190216935A1 Date Published 2019-07-18), Hermanson (Bioconjugate Techniques (Third Edition), Academic Press, 2013, Pages 465-505 Chapter 11) and Minn et al. (The Lancet Oncology, Volume 20, Issue 8, e443 - e451, 2019).
All patented claims are drawn to a method of killing cancer cells or treating a patient for cancer comprising administering (i) an amount of a conjugate comprising a folate linked to fluorescein isothiocyanate (FITC) by a linker; and (ii) a CAR T cell composition comprising CAR T cells that specifically binds FITC.
However, the copending claims do not specifically recite the combination cancer therapy wherein the CAR binds a cell-surface antigen on an immunosuppressive cell or a cancer cell with specificity, or wherein the recognition region is a single chain variable fragment (scFv) of an antibody that binds to a cell-surface antigen with high specificity, or wherein the cell-surface antigen is CD19. They also do not specifically teach combination cancer therapy wherein: the recognition region is a scFv region of an anti-FITC antibody, the co-stimulation domain is CD28, and the activation signaling domain is a T cell CD3ζ chain; the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD137 (4-1BB), and the activation signaling domain is a T cell CD3 ζ chain; or the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD28, and the activation signaling domain is a T cell CD3 ζ chain. They further do not specifically teach the combination cancer therapy wherein the linker is (PEG)3. They do not specifically teach the combination cancer therapy wherein the drug moiety in the at least one SMDC is an agonist of a pattern recognition receptor located in the endosome or the cytoplasm of a cell, or wherein the drug moiety in the at least one SMDC is an agonist of a toll-like receptor (TLR), or wherein the SMDC is a folate-TLR7 agonist, a releasable form of a folate-(PEG)3-TLR7 agonist, or a non-releasable form of a folate-(PEG)3-TLR7 agonist.
They also do not specifically teach the method wherein administering the combination cancer therapy increases an amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to an amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME, or wherein administering the combination cancer therapy reduces an amount of myeloid-derived suppressor cells present within a TME of the subject. They also do not specifically teach he method wherein the cancer is a solid tumor cancer and further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy.
However, these deficiencies are made up in the teachings of Low et al., Yi, Siwowska et al., Hermanson, Low (2) et al., Chi et al. and Minn et al.
The teachings of Low et al., Yi, Siwowska et al., Hermanson, Low (2) et al., Chi et al. and Minn et al. are discussed above.
It would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer wherein the anti-FITC CAR recited in the patents are substituted with anti-CD19 CAR as taught by Low et al. (paragraph [0004]) to arrive at a CAR that binds CD19, which is a cell-surface tumor associated antigen expressed on malignant B cells also as taught by Low et al. (paragraph [0004]) because Low et al. teaches that patients treated with anti-CD 19 CAR experienced remission of disease (paragraph [0004]). One can further substitute the co-stimulation domain of 4-1BB with the co-stimulation domain of CD28 also as taught by Low et al. (paragraph [0029]) with a reasonable expectation of success that such a construct will produce functional anti-CD19 CAR-expressing cytotoxic lymphocytes because Low et al. teaches that the co-stimulation domains 4-1BB (CD137), CD28 or CD134 have been included in second generation CARs to achieve prolonged activation of T cells (paragraph [0003]).
Also, it would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer wherein the PEG linkers recited in the patents were substitute with the PEG3 linker taught by Hermanson as the linker for the FITC-Folate SMDC because Hermanson teaches that small molecule conjugates that comprises PEG3 linkers have increased water solubility and such conjugates have been successfully used for biological labelling without causing toxicity to the organisms (Pg. 498 column left paragraph second, Pg. 504 column right paragraph second and Pg. 505 column left paragraph second).
Further, it would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer by substituting the FITC in the FITC-folate conjugate recited in the patents with the drug moiety of TLR7 agonist as taught by Low (2) et al. because Low (2) et al. teaches that the conjugate of FA-TLR7 agonist dramatically reduced the cell population of FR+ TAMs/MDSCs in 4T1 solid tumor (paragraph [0208] and FIG. 24) and that reducing immunosuppressive MDSCs in the TME can result in the inhibition of tumor growth, or the complete or partial elimination of a tumor (paragraph [0158]). With regards to claims 41 and 42, since Low (2) et al. teaches that the effect of FA-TLR7 agonist is to dramatically decrease the population of TAMs/MDSCs in 4T1 solid tumor (paragraph [0206]), and the targeting of FR+ TAMs/MDSCs in 4T1 solid tumor with FA-TLR7 agonist treatment resulted in converting the immunosuppressive M2 macrophages environment to an anti-cancer M1 macrophages environment (paragraph [0219]), it would be reasonable to expect that the combination of a folate-TLR7 agonist(SMDC) and a CAR-expressing cytotoxic lymphocyte, would also increase the amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to the amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME, or reduce the amount of myeloid-derived suppressor cells (MSDCs) present within a TME of the subject.
Even further, it would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy because Minn et al. teaches that combining CAR T cell therapy with imaging of solid tumors can enable improved tumor eradication of the CAR T-cell therapy (Summary).
Nineteenth and Twentieth NSDP Application No. 18/915,595 and 18/914,891
Claims 1, 2, 4, 7, 12, 20, 22, 25, 26, 31-33, 40 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 49-57 and 63-67 of Application No. 18/915,595;
claims 2-7, 10, 12, 15, 17, 20-22, 25 and 28-32 of Application No 18/914,891;
Although the claims at issue are not identical, they are not patentably distinct from each other because all copending claims are drawn to a method of killing cancer cells or treating cancer comprising administering (i) an amount of a conjugate comprising a folate linked via a linker to a targeting moiety that is FITC; and (ii) a CAR T cell composition comprising a CAR T cell.
In addition, copending 18/915,595 claim 53 recites the CAR is a single chain fragment variable (scFv) region of an anti-FITC antibody.
Further, copending specifications disclose the following:
Application 18/915595 specification discloses:
[00108] SCM formation may be administered prior to, simultaneous with, or after the lymphocyte formulation;
[00105] T cell formulation can be administered to the subject via suitable means, such as parenteral administration, e.g., intradermally, subcutaneously, intramuscularly, intraperitoneally, intravenously, or intrathecally;
[00107] SCM will be prepared in a formulation appropriate for the subject receiving the molecules.
Application 18/914891 specification discloses:
Pg. 6 clause 20: The method wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, an unnatural peptidoglycan, a polyvinylpyrrolidone, and/or pluronic F-127;
Pg. 26: cytotoxic T cells are transformed to express a CAR that comprises anti-FITC scFv;
Pg. 8 clause 36: The method wherein the cancer is a folate receptor expressing cancer;
Pg. 15: The terms "administer," administering," or "administered" mean all means of introducing the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or CAR T cell composition described herein to the patient, including, intravenous (iv), intramuscular (im), and subcutaneous (sc);
Pg. 43-44: The small molecule ligand linked to the targeting moiety can be administered before or after the CAR T cells;
Pg. 9 clause 43: The method wherein the CAR has a co-stimulation domain and the co-stimulation domain is selected from CD28, CD137 (4-1BB), CD134 (0X40), and CD278 (ICOS);
Pg. 9 clause 45: The method wherein the CAR has a recognition region and the recognition region is a single chain fragment variable (scFv) region of an anti-FITC antibody,
This is a provisional nonstatutory double patenting rejection.
Twenty-first and Twenty-second NSDP Application No. 18/915,595 and 18/914,891
Claims 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 30-33, 39 and 40-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 49-57 and 63-67 of Application No. 18/915,595;
claims 2-7, 10, 12, 15, 17, 20-22, 25 and 28-32 of Application No 18/914,891;
in view of Low et al. (WO2014100615A1 Date Published 2014-06-26), Yi (Immune Netw 2016 Dec;16(6):337-343), Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72), Low (2) et al. (US20190216935A1 Date Published 2019-07-18), Hermanson (Bioconjugate Techniques (Third Edition), Academic Press, 2013, Pages 465-505 Chapter 11) and Minn et al. (The Lancet Oncology, Volume 20, Issue 8, e443 - e451, 2019).
Copending claims are drawn to a method of killing cancer cells or treating cancer comprising administering (i) an amount of a conjugate comprising a folate linked via a linker to a targeting moiety that is FITC; and (ii) a CAR T cell composition comprising a CAR T cell.
However, the copending claims do not specifically recite the combination cancer therapy wherein the CAR binds a cell-surface antigen on an immunosuppressive cell or a cancer cell with specificity, or wherein the recognition region is a single chain variable fragment (scFv) of an antibody that binds to a cell-surface antigen with high specificity, or wherein the cell-surface antigen is CD19. They also do not specifically teach combination cancer therapy wherein: the recognition region is a scFv region of an anti-FITC antibody, the co-stimulation domain is CD28, and the activation signaling domain is a T cell CD3ζ chain; the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD137 (4-1BB), and the activation signaling domain is a T cell CD3 ζ chain; or the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD28, and the activation signaling domain is a T cell CD3 ζ chain. They further do not specifically teach the combination cancer therapy wherein the linker is (PEG)3. They do not specifically teach the combination cancer therapy wherein the drug moiety in the at least one SMDC is an agonist of a pattern recognition receptor located in the endosome or the cytoplasm of a cell, or wherein the drug moiety in the at least one SMDC is an agonist of a toll-like receptor (TLR), or wherein the SMDC is a folate-TLR7 agonist, a releasable form of a folate-(PEG)3-TLR7 agonist, or a non-releasable form of a folate-(PEG)3-TLR7 agonist.
They also do not specifically teach the method wherein administering the combination cancer therapy increases an amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to an amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME, or wherein administering the combination cancer therapy reduces an amount of myeloid-derived suppressor cells present within a TME of the subject. They also do not specifically teach he method wherein the cancer is a solid tumor cancer and further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy.
However, these deficiencies are made up in the teachings of Low et al., Yi, Siwowska et al., Hermanson, Low (2) et al., Chi et al. and Minn et al.
The teachings of Low et al., Yi, Siwowska et al., Hermanson, Low (2) et al., Chi et al. and Minn et al. are discussed above.
It would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer wherein the anti-FITC CAR recited in the patents are substituted with anti-CD19 CAR as taught by Low et al. (paragraph [0004]) to arrive at a CAR that binds CD19, which is a cell-surface tumor associated antigen expressed on malignant B cells also as taught by Low et al. (paragraph [0004]) because Low et al. teaches that patients treated with anti-CD 19 CAR experienced remission of disease (paragraph [0004]). One can further substitute the co-stimulation domain of 4-1BB with the co-stimulation domain of CD28 also as taught by Low et al. (paragraph [0029]) with a reasonable expectation of success that such a construct will produce functional anti-CD19 CAR-expressing cytotoxic lymphocytes because Low et al. teaches that the co-stimulation domains 4-1BB (CD137), CD28 or CD134 have been included in second generation CARs to achieve prolonged activation of T cells (paragraph [0003]).
Also, it would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer wherein the PEG linkers recited in the patents were substitute with the PEG3 linker taught by Hermanson as the linker for the FITC-Folate SMDC because Hermanson teaches that small molecule conjugates that comprises PEG3 linkers have increased water solubility and such conjugates have been successfully used for biological labelling without causing toxicity to the organisms (Pg. 498 column left paragraph second, Pg. 504 column right paragraph second and Pg. 505 column left paragraph second).
Further, it would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer by substituting the FITC in the FITC-folate conjugate recited in the patents with the drug moiety of TLR7 agonist as taught by Low (2) et al. because Low (2) et al. teaches that the conjugate of FA-TLR7 agonist dramatically reduced the cell population of FR+ TAMs/MDSCs in 4T1 solid tumor (paragraph [0208] and FIG. 24) and that reducing immunosuppressive MDSCs in the TME can result in the inhibition of tumor growth, or the complete or partial elimination of a tumor (paragraph [0158]). With regards to claims 41 and 42, since Low (2) et al. teaches that the effect of FA-TLR7 agonist is to dramatically decrease the population of TAMs/MDSCs in 4T1 solid tumor (paragraph [0206]), and the targeting of FR+ TAMs/MDSCs in 4T1 solid tumor with FA-TLR7 agonist treatment resulted in converting the immunosuppressive M2 macrophages environment to an anti-cancer M1 macrophages environment (paragraph [0219]), it would be reasonable to expect that the combination of a folate-TLR7 agonist(SMDC) and a CAR-expressing cytotoxic lymphocyte, would also increase the amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to the amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME, or reduce the amount of myeloid-derived suppressor cells (MSDCs) present within a TME of the subject.
Even further, it would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy because Minn et al. teaches that combining CAR T cell therapy with imaging of solid tumors can enable improved tumor eradication of the CAR T-cell therapy (Summary).
This is a provisional nonstatutory double patenting rejection.
Twenty-third, Twenty-fourth and Twenty-fifth NSDP Application Nos. 18/963,158, 18/494,613 and 17/905,748
Claims 1, 2, 4, 7, 12, 20, 22, 25, 26, 31-33, 40 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-11 of Application No. 18/963,158;
claims 1-16 and 19 of Application No 18/494,613; and
claims 89, 90, 93, 94, 99, 101, 102,103, 104, 106, 107, 110, 114, 115, 117, 118 of Application No. 17/905,748
Although the claims at issue are not identical, they are not patentably distinct from each other because copending claims are drawn to a method of treating cancer comprising administering to a patient or subject (i) an amount of a conjugate comprising a small molecule ligand linked to a targeting moiety by a linker; and (ii) a CAR T cell composition comprising CAR T cells that specifically binds to the targeting moiety.
In addition, copending 18/494,613 claim 2 recites the targeting moiety is FITC. Copending 18/494,613 claim 10 recites wherein the small molecule ligand of the compound is a folate. copending 18/494,613 claims 12 and 13 recite wherein the CAR T cells comprise an anti-FITC antibody or fragment thereof that is a single chain fragment variable (scFv) region.
Further, copending 17/905,748 claim 94 recites the targeting moiety is FITC. Copending 17/905,748 claims 101 and 103 recite the CAR has a recognition region comprising a single chain fragment variable (scFv) region of an anti-FITC antibody that binds to the targeting moiety. Copending 17/905,748 claim 93 recites small molecule ligand is folate.
Moreover, copending specifications disclose the following:
Copending 18/963,158 specification discloses:
Clause 60: The method wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, an unnatural peptidoglycan, a polyvinylpyrrolidone, pluronic F-127, or a combination thereof;
Pg. 45: cytotoxic T cells can be transformed to express a CAR that comprises anti-FITC scFv;
Pg. 36: the cancer is a folate receptor expressing cancer or a folate receptor α-expressing cancer or a folate receptor β-expressing cancer;
Pg. 57: the CAR T cells can be administered before or after the compound;
Pg. 20 the terms "administer," administering," or "administered" mean all means of introducing the compound, or pharmaceutically acceptable salt thereof, or CAR T cell composition described herein to the patient, including intravenous, intramuscular, and subcutaneous;
Clause 73: The method wherein the CAR has a co- stimulation domain and the co-stimulation domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (0X40), and CD278 (ICOS);
Clause 74: The method wherein the CAR has an activation signaling domain and the activation signaling domain is a T cell CD3Q chain or an Fc
Copending 18/494,613 specification discloses:
Pg. 146: cytotoxic T cells, or another type of T cell, can be transformed to express a CAR that comprises anti-FITC scFv;
Pg. 11 clause 28: The method wherein the cancer is a folate receptor expressing cancer;
Pg. 137: the cancer is a folate receptor α-expressing cancer or a folate receptor β-expressing cancer;
Pg. 74: As used herein, the terms "administer," administering," or "administered" mean all means of introducing the compound, or pharmaceutically acceptable salt thereof, or CAR T cell composition described herein to the patient, including, intravenous, intramuscular and subcutaneous.
Copending 17/905,748 specification discloses:
Pg. 22: cytotoxic T cells, or another type of T cell, can be transformed to express a CAR that comprises anti-FITC scFv;
Pg. 61 paragraph [0195]: the cancer is a folate receptor expressing cancer, a folate receptor α-expressing cancer; or a folate receptor β-expressing cancer;
Pg. 66 paragraph [0214]: Where a method of therapy comprises administering more than one treatment, compound, or composition to a subject, it will be understood that the order, timing, number, concentration, and volume of the administration is limited only by the medical requirements and limitations of the treatment (i.e. two treatments can be administered to the subject, e.g., simultaneously, consecutively, sequentially, alternatively, or according to any other regimen);
Pg. 51: The term "administering," and its formatives, generally refer to any and all means of introducing the compounds and compositions described herein (e.g., the CAR-T cell compositions, the adaptor compound(s) or the pharmaceutically acceptable salt(s) thereof, and/or the activity modifying compounds) to a cell, tissue, organ, or biological fluid of a subject;
Pg. 11 paragraph [0030]: The CAR can further comprise a co-stimulation domain and/or an activation signaling domain. In certain embodiments, the co-stimulation domain is selected from a group consisting of CD28, CD137 (4-1BB), CD134 (0X40), and CD278 (ICOS).
This is a provisional nonstatutory double patenting rejection.
Twenty-sixth, Twenty-seventh and Twenty-eighth NSDP Application Nos. 18/963,158, 18/494,613 and 17/905,748
Claims 1, 2, 4-7, 12, 13, 16, 18-20, 22, 25, 26, 30-33, 39 and 40-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-11 of Application No. 18/963,158;
claims 1-16 and 19 of Application No 18/494,613; and
claims 89, 90, 93, 94, 99, 101, 102,103, 104, 106, 107, 110, 114, 115, 117, 118 of Application No. 17/905,748
in view of Low et al. (WO2014100615A1 Date Published 2014-06-26), Yi (Immune Netw 2016 Dec;16(6):337-343), Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72), Low (2) et al. (US20190216935A1 Date Published 2019-07-18), Hermanson (Bioconjugate Techniques (Third Edition), Academic Press, 2013, Pages 465-505 Chapter 11) and Minn et al. (The Lancet Oncology, Volume 20, Issue 8, e443 - e451, 2019).
Copending claims are drawn to a method of treating cancer comprising administering to a patient or subject (i) an amount of a conjugate comprising a small molecule ligand linked to a targeting moiety by a linker; and (ii) a CAR T cell composition comprising CAR T cells that specifically binds to the targeting moiety.
In addition, copending 18/494,613 claim 2 recites the targeting moiety is FITC. Copending 18/494,613 claim 10 recites wherein the small molecule ligand of the compound is a folate. copending 18/494,613 claims 12 and 13 recite wherein the CAR T cells comprise an anti-FITC antibody or fragment thereof that is a single chain fragment variable (scFv) region.
Further, copending 17/905,748 claim 94 recites the targeting moiety is FITC. Copending 17/905,748 claims 101 and 103 recite the CAR has a recognition region comprising a single chain fragment variable (scFv) region of an anti-FITC antibody that binds to the targeting moiety. Copending 17/905,748 claim 93 recites small molecule ligand is folate.
However, the copending claims do not specifically recite the combination cancer therapy wherein the CAR binds a cell-surface antigen on an immunosuppressive cell or a cancer cell with specificity, or wherein the recognition region is a single chain variable fragment (scFv) of an antibody that binds to a cell-surface antigen with high specificity, or wherein the cell-surface antigen is CD19. They also do not specifically teach combination cancer therapy wherein: the recognition region is a scFv region of an anti-FITC antibody, the co-stimulation domain is CD28, and the activation signaling domain is a T cell CD3ζ chain; the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD137 (4-1BB), and the activation signaling domain is a T cell CD3 ζ chain; or the recognition region is a scFv region of an anti-CD19 antibody, the co-stimulation domain is CD28, and the activation signaling domain is a T cell CD3 ζ chain. They further do not specifically teach the combination cancer therapy wherein the linker is (PEG)3. They do not specifically teach the combination cancer therapy wherein the drug moiety in the at least one SMDC is an agonist of a pattern recognition receptor located in the endosome or the cytoplasm of a cell, or wherein the drug moiety in the at least one SMDC is an agonist of a toll-like receptor (TLR), or wherein the SMDC is a folate-TLR7 agonist, a releasable form of a folate-(PEG)3-TLR7 agonist, or a non-releasable form of a folate-(PEG)3-TLR7 agonist.
They also do not specifically teach the method wherein administering the combination cancer therapy increases an amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to an amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME, or wherein administering the combination cancer therapy reduces an amount of myeloid-derived suppressor cells present within a TME of the subject. They also do not specifically teach he method wherein the cancer is a solid tumor cancer and further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy.
However, these deficiencies are made up in the teachings of Low et al., Yi, Siwowska et al., Hermanson, Low (2) et al., Chi et al. and Minn et al.
The teachings of Low et al., Yi, Siwowska et al., Hermanson, Low (2) et al., Chi et al. and Minn et al. are discussed above.
It would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer wherein the anti-FITC CAR recited in the patents are substituted with anti-CD19 CAR as taught by Low et al. (paragraph [0004]) to arrive at a CAR that binds CD19, which is a cell-surface tumor associated antigen expressed on malignant B cells also as taught by Low et al. (paragraph [0004]) because Low et al. teaches that patients treated with anti-CD 19 CAR experienced remission of disease (paragraph [0004]). One can further substitute the co-stimulation domain of 4-1BB with the co-stimulation domain of CD28 also as taught by Low et al. (paragraph [0029]) with a reasonable expectation of success that such a construct will produce functional anti-CD19 CAR-expressing cytotoxic lymphocytes because Low et al. teaches that the co-stimulation domains 4-1BB (CD137), CD28 or CD134 have been included in second generation CARs to achieve prolonged activation of T cells (paragraph [0003]).
Also, it would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer wherein the PEG linkers recited in the patents were substitute with the PEG3 linker taught by Hermanson as the linker for the FITC-Folate SMDC because Hermanson teaches that small molecule conjugates that comprises PEG3 linkers have increased water solubility and such conjugates have been successfully used for biological labelling without causing toxicity to the organisms (Pg. 498 column left paragraph second, Pg. 504 column right paragraph second and Pg. 505 column left paragraph second).
Further, it would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer by substituting the FITC in the FITC-folate conjugate recited in the patents with the drug moiety of TLR7 agonist as taught by Low (2) et al. because Low (2) et al. teaches that the conjugate of FA-TLR7 agonist dramatically reduced the cell population of FR+ TAMs/MDSCs in 4T1 solid tumor (paragraph [0208] and FIG. 24) and that reducing immunosuppressive MDSCs in the TME can result in the inhibition of tumor growth, or the complete or partial elimination of a tumor (paragraph [0158]). With regards to claims 41 and 42, since Low (2) et al. teaches that the effect of FA-TLR7 agonist is to dramatically decrease the population of TAMs/MDSCs in 4T1 solid tumor (paragraph [0206]), and the targeting of FR+ TAMs/MDSCs in 4T1 solid tumor with FA-TLR7 agonist treatment resulted in converting the immunosuppressive M2 macrophages environment to an anti-cancer M1 macrophages environment (paragraph [0219]), it would be reasonable to expect that the combination of a folate-TLR7 agonist(SMDC) and a CAR-expressing cytotoxic lymphocyte, would also increase the amount of myeloid cells exhibiting an immune-stimulating phenotype in a tumor microenvironment (TME) of the subject as compared to the amount of myeloid cells exhibiting an immunosuppressive phenotype in the TME, or reduce the amount of myeloid-derived suppressor cells (MSDCs) present within a TME of the subject.
Even further, it would be obvious to perform a combined method to generate and administer the products of the patented claims for a method of treating a subject for cancer further comprising imaging the solid tumor cancer prior to or during administering the combination cancer therapy because Minn et al. teaches that combining CAR T cell therapy with imaging of solid tumors can enable improved tumor eradication of the CAR T-cell therapy (Summary).
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642