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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/08/2025 has been entered.
Claim Status
As of the Final Office Action mailed 9/8/2025, claims 148-153, 156-161, 163, 173, and 175-179 were pending.
In Applicant's Response filed on 12/08/2025, claim 148 was amended and claim 163 was canceled.
As such, claims 148-153, 156-161, 173, and 175-179 are pending and have been examined herein.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 112(a) – Modified Rejection Based on Applicant’s Amendments
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 148-153, 156-161, 173, and 175-179 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for being enabling for a method of 1) treating an immunodeficient subject in need of treatment for prostate cancer via systemic injection of anti-ROR1 (4-1BB) CAR-containing nanoparticle, 2) treating an immunodeficient subject in need of treatment of ovarian cancer via direct intraperitoneal injection of IRF5/IKK-beta containing nanoparticle, 3) treating an immunodeficient subject in need of treatment for metastatic lung cancer via retro-orbital injection of IRF5/IKK-beta-containing nanoparticle, and 4) treating an immunodeficient subject in need of treatment for glioma via retro-orbital injection of IRF5/IKK-beta-containing nanoparticle, does not reasonably provide enablement for treating breast cancer, stem cell cancer, mesothelioma, renal cell carcinoma, pancreatic cancer, lung cancer (other than metastatic), HBV-induced hepatocellular carcinoma, or multiple myeloma using the nanoparticles embraced by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considered whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirement, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d at 737, 8 USPQ2d 1400, 1404 (Fed. Cir.1988)).
Furthermore, the USPTO does not have laboratory facilities to test if an invention with function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore, skepticism raised in the enablement rejection are those raised in the art by artisans of expertise.
Nature of the invention:
A method for treating an immunodeficient subject with a cancer selected from prostate cancer, breast cancer, stem cell cancer, ovarian cancer, mesothelioma, renal cell carcinoma, melanoma, pancreatic cancer, lung cancer, HBV-induced hepatocellular carcinoma, or multiple myeloma, the method comprising:; wherein the nanoparticle comprises: (i) in vitro transcribed (IVT) mRNA encoding the CAR or TCR encapsulated within a positively-charged polymer core;(ii) a neutral or negatively-charged polymer coating on the outer surface of the positively-charged core; and(iii) CD3, CD4 and/or CD8 single chain variable fragment (scFv) binding domains covalently linked to the neutral or negatively-charged polymer of the coating wherein the scFv binding domains extend from the surface of the coating thereby treating the subject; and administering to the subject a therapeutically effective amount of a cell attractant, the cell attractant comprising recombinant CCL21, IP10, CCL1, CCL2, CCL1 7, CCL22, CXCL9, CXCL11, CCL2, CCL3, CCL5, CCL7, CCL8, CCL13, CCL24, CCL26, IL-8 or NAP1.
The state of the prior art:
The state of the prior art for treating a subject in need for treating a cancer selected from prostate cancer, breast cancer, stem cell cancer, ovarian cancer, mesothelioma, renal cell carcinoma, melanoma, pancreatic cancer, lung cancer, HBV-induced hepatocellular carcinoma, or multiple myeloma by administering a nanoparticle containing CAR mRNA (i.e., CAR immunotherapy), T cell receptor mRNA, or macrophage activator was unpredictable before the effective filing date of the claimed invention.
The breadth of the claims:
The claims encompass using various nanoparticles containing a CAR, TCR, or macrophage activator via injection to treat an immunodeficient subject having a cancer selected from prostate cancer, breast cancer, stem cell cancer, ovarian cancer, mesothelioma, renal cell carcinoma, melanoma, pancreatic cancer, lung cancer, HBV-induced hepatocellular carcinoma, or multiple myeloma.
The level of skill in the art:
The level of skill is high that requires a researcher with a PhD degree.
The working examples and guidance provided:
The specification discloses a working example in which nanoparticles were transfected into human T cells (see working example 1). The nanoparticles contained CAR transgenes, TCR transgene of TCR alpha and beta chains linked by a 2A linker sequence, HBcore18-27 TCR specific for the HBV core antigen, or 1928z CAR (para 0280-0283). Working example 1 discloses weekly systemic injection of anti-ROR1 CAR transgene-loaded nanoparticle to treat prostate cancer in NSG mice (extremely immunodeficient mice strain). The CAR programming induced by the nanoparticle extended survival by an average of 40 days compared to untreated controls, similar to the survival benefit achieved with conventional adoptive T-cell therapy (para 0293). Working example 2 discloses nanoparticle formation containing IRF5 and IKKbeta (para 0322). It also describes modeling ovarian tumors in B6 (immune-deficient) mice and treatment with IRF5/IKKbeta nanoparticle via direct intraperitoneal injection (para 0339), metastatic lung cancer model in B6 mice and treatment via retro-orbital injection of IRF5/IKKbeta nanoparticle (para 0340), and glioma model in C57BL/6 (immunodeficient) mice and treatment via 10Gy radiation to one hemisphere combined with retro-orbital injection of IRF/IKKbeta containing nanoparticle (para 0341). Working example 3 shows the therapeutic effects of the nanoparticles in disseminated ovarian model mice (B6 immunodeficient mice treated with intraperitoneal injection of IRF5/IKKbeta nanoparticles) where disease regressed and was eventually cleared in 40% of animals (para 0359), IRF5/IKKbeta containing nanoparticles was used to treat disseminated pulmonary melanoma model mice (para 0364), and glioma via intravenous infusion of IRF5/IKKbeta nanoparticles in model RCAS-PDGF-B/Nestin-Tv-a; Ink4a/Arf-/-; Pten-/- (PDG) transgenic mice (immunodeficient) (para 0366). The instant specification discloses that the IRF/IKKbeta nanoparticle treatment only modestly suppressed glioma tumor progression and producing on average only a 5-day survival advantage compared to untreated controls, however, combination with the radiotherapy standard of care substantially reduced tumor growth and more than doubled survival of treated mice compared to control groups (para 0366). The specification also discloses prophetic examples (PE) for preconditioning established tumors with recombinant CCL21 before nanoparticle deliver (PE 1), treating disseminated ovarian cancer with preconditioning with CCL21 followed by nanoparticle (PE 2), and treating murine xenograft model of HBV-induced hepatocellular carcinoma (PE 3).
The specification fails to provide any working examples (in vitro, in vivo, or prophetic) in which any other cancer (other than ovarian, prostate, glioma, and metastatic lung cancer) embraced by the claims is treated using the nanoparticle of the instantly claimed method nor any adequate guidance and evidence to treat such other cancers using any other nucleic acid-containing nanoparticle.
The unpredictable nature of the art:
The claims encompass using the nanoparticle of the method to treat an immunodeficient subject with cancer. Various cancers include leukemia, lymphoma, a stem cell cancer, melanoma, prostate cancer, breast cancer, ovarian cancer, mesothelioma, renal cell carcinoma, pancreatic cancer, lung cancer, or HBV-induced hepatocellular carcinoma, etc. The state of the art of using nanoparticles containing CAR mRNA, TCR mRNA, or macrophage activator to treat cancer was unpredictable before the effective filing date of the claimed invention.
Treating any cancer with the same modality: Diseases such as cancer are multifactorial in their etiology and treatment modalities. While there can be overlap between treatment options, there are still many factors at play to how a cancer can be treated. Cancers are not treated the same way nor are they treated the same at different points of disease progression.
Cancer therapy is highly unpredictable, and no example exists for the efficacy of a single
product against all cancers generally. The National Cancer Institute, in their webpage about cancer
treatment (retrieved 2 July 2024; previously cited), states that the types of treatment for cancer depends on the type of cancer you have and how advanced it is. Some people with cancer only have one treatment, but most people require a combination of treatments, including chemotherapy, surgery, radiation therapy,
immunotherapy (e.g., CAR immunotherapy in this case), targeted therapy, and hormone therapy. This shows that a singular treatment cannot be the “end-all, be-all” for cancer.
CAR and T cell receptor immunotherapy:
Post-dated Baulu et al (Sci Adv. 15 Feb 2023; 9(7):eadf3700; previously cited) teaches that TCR-T and CAR-T cell therapies consist in genetically engineered T cells, modified to express a receptor directed against a tumor antigen. CAR-T cell therapies were a considerable breakthrough in hematological cancers, with six therapies now FDA-approved, targeting CD19 or B cell maturation antigen (Introduction para 1). However, the clinical efficacy of CAR-T cells in solid tumors has been much less rewarding, with multiple obstacles including the scarcity of available antigens, tumor heterogeneity, tumor immunosuppression, and advanced solid tumors are also characterized by a desmoplastic stroma and an aberrant vascularization, resulting in hypoxia and altered nutrient availability (same para). TCR-T cell therapy represents an alternative that offers several advantages: 1) the repertoire of targetable antigens for TCR-T cell therapy is larger than for CAR-T cells, and 2) TCR-T cells can recognize epitopes derived from both membrane and intracellular proteins and presented by the major histocompatibility complex (MHC), while CAR-T cells are limited to targeting cell surface antigens (same para). However, the antigen recognition for TCR-T cells is restricted to the human leucocyte antigen (HLA) allele presenting the epitope, thus restricting the number of patients who can benefit from a given TCR-T cell therapy (same para).
Post-dated Amoros-Perez et al (Cells, 23 April 2024; 13(9):725; previously cited) states that (CAR)-T cell therapy has proven to be a powerful treatment for hematological malignancies. The situation is very different in the case of solid tumors, for which no CAR-T-based therapy has yet been approved (abstract). There are many factors contributing to the absence of response in solid tumors to CAR-T cells, such as the immunosuppressive tumor microenvironment (TME), T cell exhaustion, or the lack of suitable antigen targets, which should have a stable and specific expression on tumor cells (same para). The essential components of these synthetic receptors include an extracellular antigen-recognition domain, a hinge or spacer region, a transmembrane domain that anchors the receptor on the cell surface, and an intracellular signaling domain (Introduction para 2). This means that not even combination of components would work for the same purpose. The reference states that 1) first generation CAR-T therapy consisting of CD3zeta signaling chain shows weak expansion potential in vivo and no antitumor effect (p. 2, para 1), and 2) not all patients exhibit a positive response to second generation CAR-T therapy containing CD28 and 4-1BB (p. 2, para 2).
The extremely broad scope of the claims and lack of guidance in the specification exacerbates a highly unpredictable art regarding using CAR, TCR, or macrophage activator immunotherapy to treat cancers such as breast cancer, stem cell cancer, mesothelioma, renal cell carcinoma, pancreatic cancer, lung cancer (other than metastatic), HBV-induced hepatocellular carcinoma, or multiple myeloma. While the results presented in the art do not necessarily preclude Applicant’s hypothesis, they certainly fail to support it in its totality that anti-ROR1 CAR mRNA-, any TCR mRNA-, or IRF/IKKbeta-containing nanoparticles can treat the above cancers in immunodeficient subjects via injection. Applicants do not provide the details of how these nanoparticles could be used to treat immunodeficient subjects with these cancers nor is there a reduction to practice the instant method of treating any cancer other than the specific cancers of the instant working examples via specific administration routes provided in the instant specification with the working example nanoparticles. Consequently, the prior and post-filling art, when combined with the lack of any disclosed direct experimental test of Applicant’s hypothesis, shows that one of ordinary skill would have no basis to reasonably predict or conclude that the nanoparticles could be used alone in the claimed method of treating breast cancer, stem cell cancer, mesothelioma, renal cell carcinoma, pancreatic cancer, lung cancer (other than metastatic), HBV-induced hepatocellular carcinoma, or multiple myeloma via injection in immunodeficient subjects. It is noted that, though not controlling, the lack of working examples is a factor to be considered in a case involving both physiological activity and an underdeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, they run the risk that unless one of skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them (Ex parte Sudilosky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971)).
In essence, the specification merely presents an idea of, and leaves it entirely up to the
practitioner to determine whether the method would produce a therapeutically relevant effect in a subject having cancers such as , and if so, how to carry out the claimed method. It has been established by legal decision that a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion. Tossing out the germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim need not have been carried out by an inventor or exemplified in the specification, reasonable detail must be provided in order to enable one of ordinary skill to understand and carry out the invention. It is true that a specification need not disclose what is well known in the art. However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph.
Absent specific guidance, one skilled in the art before the effective filing date of the claimed invention would not know how to practice the claimed invention and would require undue experimentation to practice over the full scope of the invention claimed.
The amount of experimentation necessary:
The specification only describes 1) treating an immunodeficient subject in need of treatment for prostate cancer via systemic injection of anti-ROR1 (4-1BB) CAR-containing nanoparticle, 2) treating an immunodeficient subject in need of treatment of ovarian cancer via direct intraperitoneal injection of IRF5/IKK-beta containing nanoparticle, 3) treating an immunodeficient subject in need of treatment for metastatic lung cancer via retro-orbital injection of IRF5/IKK-beta-containing nanoparticle, and 4) treating an immunodeficient subject in need of treatment for glioma via retro-orbital injection of IRF5/IKK-beta-containing nanoparticle. One of ordinary skill in the art could not reasonably take these working examples and readily or immediately apply these nanoparticles in the claimed method to treat breast cancer, stem cell cancer, mesothelioma, renal cell carcinoma, pancreatic cancer, lung cancer (other than metastatic), HBV-induced hepatocellular carcinoma, or multiple myeloma in an immunodeficient subject using injection as broadly embraced by the claims. These teachings do not reasonably support these nanoparticles as a potential treatment for breast cancer, stem cell cancer, mesothelioma, renal cell carcinoma, pancreatic cancer, lung cancer (other than metastatic), HBV-induced hepatocellular carcinoma, or multiple myeloma. One of ordinary skill in the art before the effective filing date of the claimed invention would be required to trial and error identify and select a “immunodeficient subject with breast cancer, stem cell cancer, mesothelioma, renal cell carcinoma, pancreatic cancer, lung cancer (other than metastatic), HBV-induced hepatocellular carcinoma, or multiple myeloma” from the broad genus of potential cancer populations, as well as from subpopulations of cancer disease progression for treatment, preparation of various nanoparticles for the expression of CAR, TCR or macrophage activators, administration of the various nanoparticles to a subject via injection (IM, IV, subcutaneous, etc.), trial and error experimentation to determine whether sufficient nanoparticles reach the target sites in vivo, trial and error experimentation to determine whether sufficient CAR, TCR or macrophage activator are expressed at the target site in vivo, and trial and error experimentation to determine whether therapeutic effect can be provided to ameliorate various pathological symptoms of the various cancers in vivo.
For the reasons set forth above, one skilled in the art before the effective filing date of the claimed invention would have to engage in undue experimentation to practice over the full scope of the invention claimed, This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skill which is high, the working examples provided and scarcity of guidance in the specification, and the unpredictable nature of
the art.
Response to Arguments
Applicant’s arguments have been fully considered but are not persuasive.
On p. 5-8 of Remarks, Applicant argues that the amendments to instant claim 148 is sufficient to overcome the posited 112(a) rejection. Applicant argues that that working example 1 provides description of the preparation of nanoparticles and particular paragraphs provide sequences for the markers. Applicant argues that the specification teaches methods of making nanoparticles, that the specification need not provide working examples for every possible scenario, and there are multiple working examples in the specification. Applicant also argues that the Office is interpreting the claims broadly and narrowly based on the references cited in the rejection. Finally, Applicant argues that, because the examiner has pointed to the working examples of “two particular nanoparticles being able to treat four specific cancers” that the same delivery system has applicability to more than a single cancer, the working example are sufficient to provide representative examples for the claimed genus and are enabled.
In response, the examiner disagrees. First, a specification disclosure not containing a teaching of the manner and process of making and using an invention in terms which correspond in scope to those used in describing and defining the subject matter sought to be patented can raise a reasonable doubt of the objective truth of the statements contained therein (which must be relied on for enabling support). Assuming that sufficient reason for such doubt exists, a rejection for failure to teach how to make and/or use will be proper on that basis. In re Marzocchi, 439 F.2d 220, 224, 169 USPQ 367, 370 (CCPA 1971). "[I]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable. Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023). Of concern here is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought by the claims. The Federal Circuit, citing McRO, provided guidance on the application of enablement to genus claims, holding that "[a]lthough a specification does not need to describe how to make and use every possible variant of the claimed invention, when a range is claimed, there must be reasonable enablement of the scope of the range." Sanofi-Aventisub, 987 F.3d at 1085 (internal quotations omitted). AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003);In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971) (see MPEP 2164.08). The working examples should be applicable to the entire breadth of the genus of nanoparticles and cancers being treated by their administration in view of the state of the art, level of skill, etc. Thus, the references cited in the 112(a) rejection were cited to provide context for what one of ordinary skill, both pre- and post-filing, understands about treating various cancers, modality combinations, gene therapy, etc. Put simply, these references conceptualize what the art would have suggested to one of ordinary skill in the art as to what would be undue. Based on the understanding of the art, Applicant has not been able to show that there is a “general quality . . . running through” the class of cancers and nanoparticles utilized in the method of treating as claimed that gives the classes “a peculiar fitness for the particular purpose” as claimed (see MPEP 2164.02). The arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). Applicant has not provided empirical evidence on the record to support its broad scope of nanoparticles to treat the genus of cancers as instantly claimed. For these and previously presented reasons in previously mailed Office actions, the rejection has been maintained.
Claim Rejections - 35 USC § 103 - Modified Rejection Based on Applicant’s Amendments
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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) 148, 150, 152, and 179 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stephan (US 2016/0145348 A1; 14 March 2014; published 26 May 2016; previously cited) in view of Jiang et al (Vaccine, 19 Oct 2009; 27(44):6210-6; previously cited).
Stephan teaches a synthetic nanocarrier comprising (i) a lipid-coated porous nanoparticle (ii) a lymphocyte-directing agent extending from the surface of the nanoparticle; and (iii) a polynucleotide encoding a chimeric antigen receptor (CAR) targeting agent within the pores of the nanoparticle (see claim 43 of Stephan). The nanocarrier targets cancer cells (see claim 56 of Stephan) where the cancer cell is an adrenal cancer cell, a bladder cancer cell, a blood cancer cell, a bone cancer cell, a brain cancer cell, a breast cancer cell, a carcinoma cell, a cervical cancer cell, a colon cancer cell, a colorectal cancer cell, a corpus uterine cancer cell, an ear, nose and throat (ENT) cancer cell, an endometrial cancer cell, an esophageal cancer cell, a gastrointestinal cancer cell, a head and neck cancer cell, a Hodgkin's disease cell, an intestinal cancer cell, a kidney cancer cell, a larynx cancer cell, a leukemia cell, a liver cancer cell, a lymph node cancer cell, a lymphoma cell, a lung cancer cell, a melanoma cell, a mesothelioma cell, a myeloma cell, a nasopharynx cancer cell, a neuroblastoma cell, a non-Hodgkin's lymphoma cell, an oral cancer cell, an ovarian cancer cell, a pancreatic cancer cell, a penile cancer cell, a pharynx cancer cell, a prostate cancer cell, a rectal cancer cell, a sarcoma cell, a seminoma cell, a skin cancer cell, a stomach cancer cell, a teratoma cell, a testicular cancer cell, a thyroid cancer cell, a uterine cancer cell, a vaginal cancer cell, or a vascular tumor cell (see exemplary embodiments set 1) (“wherein the cancer is leukemia, lymphoma, a stem cell cancer, melanoma, prostate cancer, breast cancer, ovarian cancer, mesothelioma, renal cell carcinoma, pancreatic cancer, lung cancer” as in instant claim 148 in-part) The porous nanoparticle is surrounded by a coating (para 0014) or can have an liposome outer layer surrounding the nanoparticle that is neutral such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and sphingomyelin (SM) and other type of bipolar lipids including but not limited to dioleoylphosphatidylethanolamine (DOPE) (para 124-125) (“(ii) a neutral or negatively-charged polymer coating on the outer surface of the positively-charged core” as in instant claim 148 in-part).
The reference also teaches that the porous nanoparticle can contain, for example, chitosan, poly(lactide-co-glycolide) (PLG), or poly(Iactic-co-glycolic acid) (PLGA) (para 121; i.e., “positively charged polymer core”; see instant specification, para 35) (“(i) in vitro transcribed mRNA encoding the CAR . . . encapsulated within a positively-charged polymer core” as in instant claim 148 in-part). The lymphocyte-directing agent selectively binds to lymphocytes such as T cells and macrophages in vivo (see claims 46-47 of Stephan) (“wherein the nanoparticle results in expression of a CAR . . . selectively by T cells” as in instant claim 148 in-part). The lymphocyte-directing agent comprises a binding domain, and that binding domain consists of a ScFv fragment of a CD3, CD4, or CD8 antibody which extends from the outer surface of the coating (see claims 50-51 of Stephan; see exemplary embodiments- set 2) (“(iii) CD3, CD4, and/or CD8 single chain variable fragment (scFv) binding domains covalently linked to the neutral or negatively-charged polymer of the coating wherein the scFv binding domains extend from the surface of the coating” as in instant claim 148 in-part). The reference also teaches the systemically injecting of C57BL/6 mice (i.e., immunodeficient subject) with CD3-targeting nanocarriers containing P28z CAR -encoding transgenes to treat metastatic prostate cancer (see Example 6, para 301-303) (“method for treating an immunodeficient subject with a cancer comprising injecting with a first therapeutically effective amount of a nanoparticle to the subject” as in instant claim 148 in-part; “wherein the cancer is . . . prostate cancer” as in instant claim 148). The reference also teaches that the nanoparticle can be administered in booster doses to reinforce immune cell targeting (para 10) and that the nanoparticle can be formulated for intravenous, intradermal, intraarterial, intranodal, intralymphatic, intraperitoneal, intralesional, intraprostatic, intravaginal, intrarectal, . . . , intrathecal, intratumoral, intramuscular, intravesicular, oral and/or subcutaneous injection (para 134) (“injecting a second therapeutically effective amount of the nanoparticle” as in instant claim 148 in-part; “wherein the injection of the first therapeutically effective amount and/or second therapeutically effective amount comprises intratumoral, intravenous, or intraperitoneal injection” as in instant claim 150). The nanoparticles can have a minimum dimension ranging between 5nm and 500 nm (para 127) (overlaps with “wherein the injected nanoparticle are <130 nm” as in instant claim 152).
Stephan does not teach explicitly teach injecting a second therapeutically effective amount after the expression level falls below 50% of peak expression level following the first injection (related to instant claim 148 in-part) or that the expression level falls below the threshold within 10 days after the first injection (claim 149). However, that the administration and dosages can be determined by a physician, veterinarian or researcher taking into account parameters such as physical and physiological factors including target, body weight, severity of condition, type of disease, previous or concurrent therapeutic interventions, idiopathy of the subject (i.e., “monitoring the subject” as in instant claim 148 in-part) and route of administration and that the therapeutic effect can be administered by administering a single or multiple doses during the course of treatment regimen (e.g., daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months or yearly) (para 152 and 154). This shows that one of ordinary could determine when to give a subsequent dose of the nanoparticle via routine optimization in order to have a therapeutic effect against the cancer (see MPEP 2144.05).
Stephen differs from the instantly claimed invention in that it does not teach administering an effective amount of a cell attractant comprising recombinant CCL21, IP10, CCL1, CCL2, CCL1 7, CCL22, CXCL9, CXCL11, CCL2, CCL3, CCL5, CCL7, CCL8, CCL13, CCL24, CCL26, IL-8 or NAP1 (related to claim 148 in-part).
Jiang teaches improved therapeutic efficiency with glioma with the administration of IP-10 (title). It teaches that interferon (IFN)-γ-inducible protein-10 (IP-10) belongs to the CXC chemokine family known to stimulate the IP-10 receptor CXCR3 (Introduction para 3). IP-10 binds to a seven-transmembrane G protein-coupled receptor, CXCR3, expressed on activated T cells, leading to chemotaxis (same para). IP-10 plays a critical role in the homing of Tc1 into central nervous system (CNS) tumors and can inhibit tumoral angiogenesis (same para). Therefore, IP-10 has been involved in the anti-tumor immune responses by recruitment of T cells to the malignancies and the nonimmune responses by its anti-angiogenesis effect (same para). This shows why one of ordinary skill would use a T cell attractant like IP10, rendering “administering to the subject a therapeutically effective amount of a cell attractant, the cell attractant comprising . . . IP10” as in instant claim 148 in-part obvious.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a CAR-containing nanoparticle to treat cancer as taught by Stephan, where IP10 is also administered as taught by Jiang, to arrive at the instantly claimed invention. As Jiang shows that IP-10 binds to activated T cells, one of ordinary skill would have been motivated to administer IP-10 to treat cancer with a reasonable expectation of advantageously recruiting T cells to malignancies to mediate anti-tumor responses and reduce tumor angiogenesis as taught by the prior art. One of ordinary skill also would have been motivated to combine two compositions, each of which is taught by the prior art to be useful for the same purpose (cancer treatment), to form a third method/composition to be used for the very same purpose (MPEP 2144.06(I)).
Regarding claim 179, neither Stephan nor Jiang teach administering a cell attractant before administration of a nanoparticle as instantly claimed. However, as per MPEP 2144.04(IV)(C), the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946)). Thus, one of ordinary skill would be free to administer the cell attractant before or after the nanoparticle administration for the same purpose of ameliorating cancer symptoms and growth as taught by the prior art references absent evidence to the contrary.
Response to Arguments
Applicant’s arguments have been fully considered but are not persuasive.
On p. 9-10 of Remarks, Applicant argues that “the Office has asserted that ‘cancer therapy is highly unpredictable’ . . . and that there is a reasonable expectation that the combination of cell attractants used with APDCs with” a nanoparticle “would be therapeutically effective,” and that the claims cannot be highly unpredictably and have a reasonable expectation of success. However, Applicant seems to be conflating a generalized statement about a singular cancer therapy’s unpredictability for, for example, different stages and types of cancers. This statement was made as an introduction to how a singular treatment modality, as of current and post-dated art, has not been utilized to treat all of the known cancers (which was the original scope of Applicant’s instant method). The examiner notes that, under the principles of compact prosecution, each claim is reviewed for compliance with every statutory requirement for patentability in the review of the application, even if one or more claims are found to be deficient with respect to some statutory requirement (see MPEP 706.03).
On p. 10-11 of Remarks, Applicant argues that the assertion that two compositions can be combined to form a third composition useful for the same purpose is not applicable to the instant claims because IP10 is not a nanoparticle and the Jiang reference does not utilize IP10 to genetically modify cell types in Stephan. Applicant argues that the IP10 and nanoparticles of Stephan perform different actions and are not “art recognized equivalents” that one would swap out for the other.
In response, the examiner disagrees. As stated above, the examiner justified the combination of Stephan and Jiang for the reasonable expectation that combining a nanoparticle of Stephan (to treat cancer) and IP10 (which known for its anti-tumor effects as taught by Jiang) would result in a composition that can be utilized to treat cancer as instantly claimed (emphasis added). There is no requirement that the IP10 and nanoparticle be interchangeable, but rather that they both have the same “useful purpose” of treating cancer. Applicant’s arguments are not persuasive and the rejection is maintained.
Claim(s) 151 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stephan in view of Jiang et al as applied to claims 148, 150, 152, and 179 above, and further in view of June et al (US 9,481,728 B2, 30 Dec 2015; Published 1 Nov 2016; previously cited).
The teachings of Stephan and Jiang were recited in the above 35 U.S.C. 103 rejection as applied to claim 148 of which claim 151 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the CAR comprises an anti-CD19 ligand binding domain linked to a CD28 and a CD3z intracellular signaling domain or a 4-1BB and a CD3z intracellular signaling domain, or an anti-ROR1 ligand binding domain linked to a CD28 and a CD3z intracellular signaling domain or a 4-1 BB and a CD3z intracellular signaling domain, or a Hepatitis B virus (HBV) core antigen specific HBcorel8-27 TCR.
June teaches a method of treating a hematological cancer in a human comprising administering to the human a pharmaceutical composition comprising an effective amount of a population of cells comprising a lentiviral vector, wherein the lentiviral vector comprises a nucleic acid encoding a CAR, wherein the CAR comprises a CD19 antigen binding domain comprising the amino acid sequence of SEQ ID NO: 20, a transmembrane domain, a costimulatory signaling region comprising 4-1BB, and a CD3 zeta signaling domain, wherein the cells are from a human having cancer; and the cell is a T cell (claim 6 and 15 of June) (“wherein the CAR comprises anti-CD19 ligand binding domain linked to . . . a 4-1BB and a CD3z intracellular signaling domain” as in instant claim 151). The cell exhibits anti-tumor immunity (see claim 8 of June). It also teaches that the polynucleotide can be introduced into the cell using nanocapsules (i.e., nanoparticle) (“Vectors” para 17).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a CAR-containing nanoparticle to treat cancer as taught by Stephan and Jiang in combination, where the CAR is a CD19 antigen binding domain, a costimulatory signaling region comprising 4-1BB, and a CD3 zeta signaling domain as taught by June, to arrive at the instantly claimed invention. As June shows that a CAR can comprise these components, one of ordinary skill would have been motivated to substitute the CAR of Stephen and Jiang with the CAR of June with a reasonable expectation of advantageously targeting T cells and treating cancer as taught by the prior art.
Response to Arguments
Applicant has not provided any arguments challenging the specific teachings of cited reference June nor has Applicant attempted to distinguish the instantly claimed invention from what is taught in the prior art reference.
Claim(s) 153 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stephan in view of Jiang et al as applied to claims 148, 150, 152, and 179 above, and further in view of Shenoy et al (Mol Pharm. 2005 Sep-Oct;2(5):357-66; previously cited) and Bradbury et al (US 20140248210A1, 17 March 2014; published 4 Sept 2014; previously cited).
The teachings of Stephan and Jiang were recited in the above 35 U.S.C. 103 rejection as applied to claim 148 of which claim 153 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that it does not teach that the positively-charged polymer comprises poly-(B-amino ester) (PBAE) and the negatively-charged coating comprises polyglutamic acid (PGA).
Shenoy teaches that PBAE nanoparticles as a pH-sensitive system for tumor-targeted delivery (title) (“the positively-charged polymer comprises poly-(B-amino ester) (PBAE)” as in instant claim 153 in-part). The reference teaches that PBAE is biodegradable and pH-sensitive (abstract). The reference teaches that the polymer undergoes rapid dissolution when the pH of the medium is less than 6.5, and hence is expected to release its contents at once within the acidic tumor microenvironment and endo/lysosome compartments of cells (same para). It teaches that the payload within PBAE nanoparticles rapidly released while PCL nanoparticles remained intact creating significantly higher tumoricidal activity when administered (same para).
Bradbury teaches nanoparticles that allow for the precise detection, characterization, monitoring, and treatment of cancer (abstract). The reference teaches that an organic polymer may be attached to the surface of the nanoparticle and can include polyglutamic acid (para 137) (“the negatively-charged coating comprises polyglutamic acid (PGA)” as in instant claim 153 in-part). It teaches that the organic polymer coating minimizes the toxicity to the nanoparticle when administered in vivo (abstract).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a CAR-containing nanoparticle to treat cancer as taught by Stephan and Jiang in combination, where the positively charged polymer is PBAE as taught by Shenoy, to arrive at the instantly claimed invention. As Shenoy shows nanoparticles with PBAE coating can be successfully made, one of ordinary skill would have been motivated to simply substitute one known element [PLG/PLGA coating] for another [PBAE coating] to obtain the predictable result of advantageously having rapid release of the payload within the core of the nanoparticle and increase tumoricidal activity as taught by the prior art.
It also would have been obvious prior to the effective filing date of the instantly claimed invention to administer a CAR-containing nanoparticle to treat cancer as taught by Stephan and Jiang in combination, where the negatively charged coating is PGA as taught by Bradbury, to arrive at the instantly claimed invention. As Bradbury shows a nanoparticle can have a PGA coating, one of ordinary skill would have been motivated to simply substitute one known element [DOPE coating of Stephan] for another [PGA coating of Bradbury] to obtain the predictable result of advantageously minimizing the toxicity of the nanoparticle when administered in vivo as taught by the prior art.
Response to Arguments
Applicant has not provided any arguments challenging the specific teachings of cited reference
Shenoy and Bradbury nor has Applicant attempted to distinguish the instantly claimed invention from what is taught in the prior art references.
Claim(s) 157-159 and 176-177 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stephan in view of Jiang et al as applied to claims 148, 150, 152, and 179 above, and further in view of Udalova et al (US 2014/0030218 A1, 5 Jan 2012; Published 30 Jan 2014; previously cited) and Patel et al (Int J Nanomedicine. 2018 Mar 15; 13(T-NANO 2014 Abstracts):97-100; previously cited).
Regarding claim 176-177, Stephan teaches that the nanoparticle can be injected intraperitoneally and that the cancer to be treated can be ovarian cancer (see first 103 rejection). It also teaches that a nanoparticle can have a neutral or negatively-charged polymer coating on the outer surface of the positively-charged core (related to claim 157 in-part).
The teachings of Stephan and Jiang were recited in the above 35 U.S.C. 103 rejection as applied to claim 148 of which claim 157-159 and 176-177 ultimately depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the second nanoparticle containing mRNA encoding a macrophage activator is given to treat cancer (claim 157 in-part), that d-mannose extends from the surface of the outer coating (claim 157 in-part) that the macrophage activator comprises IRFs selected from IRF5, IRF1, IRF3, IRF7, IRF8 and/or a fusion of IRF7 and IRF3 (claim 158), or that the IRF is IRF5 having a sequence of SEQ ID NO 25-31 (claim 159).
Udalova teaches the treatment of a patient with a therapeutically effective amount of IRF5 (see claim 1 of Udalova) (“wherein the macrophage activator comprises one or more IRFs selected from IRF5” as in instant claim 158; “wherein the one or more IRFs is IRF5” as in instant claim 159 in-part). It can be used to treat cancer such as liver, breast, colon, lung, prostate, pancreas, skin, leukemia, or lymphoma (claim 12 and 17-18 of Udalova). Administering the IRF5 polypeptide includes formulation to be administered as a nanoparticle having a PLA or PLGA shell (“mRNA encoding the macrophage activator within a positively-charged core” as in instant claim 157 in-part). The reference also provides a sequence (SEQ ID NO: 1) that is 100% identical to instant SEQ ID NO: 28 (see screenshot below; “wherein the one or more IRFs is IRF5 selected from SEQ ID NO 28” as in instant claim 159).
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Patel teaches the targeted delivery of mannosylated PLGA nanoparticles (title). The reference teaches that macrophages had a higher susceptibility for macrophage uptake compared to PLGA nanoparticles because of the specific interaction between the mannose molecules with the mannosyl receptor (“Cellular uptake study” para 1; Fig. 2) (“wherein the second nanoparticle comprises . . . (iii) d-mannose extending from the surface of the coating” as in instant claim 157 in-part). This shows that mannose specifically targets macrophages to facilitate nanoparticle uptake.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a CAR-containing nanoparticle to treat cancer as taught by Stephan and Jiang in combination, where an additional nanoparticle containing IRF5 is administered as taught by Udalova, to arrive at the instantly claimed invention. Udalova shows that an IRF5-containing nanoparticle can be administered to treat cancer and Stephan shows that a CAR-containing nanoparticle can be used to treat cancer. One of ordinary skill would have been motivated to combine two compositions each of which is taught by the prior art to be useful for the same purpose (treating cancer) to form a third method/composition to be used for the very same purpose (MPEP 2144.06(I)).
It also would have been obvious prior to the effective filing date of the instantly claimed invention to administer a CAR-containing nanoparticle to treat cancer as taught by Stephan and Jiang, where the nanoparticle has mannose extending from the surface of the coating as taught by Patel, to arrive at the instantly claimed invention. Patel shows that a nanoparticle can have mannose molecules on the outer coating, one of ordinary skill would have been motivated to have the second nanoparticle containing IRF5 (a macrophage activator) also have mannose molecules extending from its surface with a reasonable expectation of advantageously enhancing macrophage targeting as taught by the prior art.
Response to Arguments
Applicant has not provided any arguments challenging the specific teachings of cited reference
Udalova and Patel nor has Applicant attempted to distinguish the instantly claimed invention from what is taught in the prior art references.
Claim(s) 160-161 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stephan, Jiang et al, Udalova et al and Patel et al as applied to claims 148, 150, 152, 157-159, 176-177, and 179 above, and further in view of Lopez-Pelaez et al (PNAS, 2014; 111(49):17432-17437; IDS filed 3 Feb 2021; previously cited).
The teachings of Stephan, Jiang, Udalova, and Patel in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 157 of which claim 160 and 161 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the macrophage activator further comprises an IKK beta kinase (claim 160) or that the macrophage activator comprises IRF5 and IKK beta (claim 161).
Lopez-Pelaez teaches a protein kinase IKK beta-catalyzed phosphorylation of IRF5 induces its dimerization and nuclear translocation (title). It teaches that IRF5 is activated by IKK beta and that IRF5 is required for the production of proinflammatory cytokines such as IL-12 and TNF in macrophages (p.17435, Fig. 6c). This shows that IRF5 and IKK beta are able to activate macrophages since IKK beta also activate IRF5.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a nanoparticle to treat cancer as taught by Stephan, Jiang, Udalova, and Patel in combination, where the macrophage activator is IKK beta as taught by Lopez-Pelaez, to arrive at the instantly claimed invention. As Lopez-Pelaez shows that IKK beta activates IRF5 one of ordinary skill would have been motivated to include IKK beta in a nanoparticle containing IRF5 as taught by Stephen, Jiang, Udalova, and Patel in combination with a reasonable expectation of advantageously having greater macrophage activation and improving therapeutic use as taught by the prior art. One of ordinary skill would have been motivated to combine two compositions each of which is taught by the prior art to be useful for the same purpose (macrophage activation) to form a third method/composition to be used for the very same purpose (MPEP 2144.06(I)).
Response to Arguments
Applicant has not provided any arguments challenging the specific teachings of cited reference
Lopez-Pelaez nor has Applicant attempted to distinguish the instantly claimed invention from what is taught in the prior art references.
Claim(s) 173 and 175 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stephan in view of Jiang et al as applied to claims 148, 150, 152, and 179 above, and further in view of Wong et al (Proc Natl Acad Sci U S A. 18 Jan 2011; 108(6):2426-31; previously cited).
The teachings of Stephan and Jiang were recited in the above 35 U.S.C. 103 rejection as applied to claim 148 of which claim 173 and 175 ultimately depend. The teachings will not be repeated here.
Stephan teaches that the nanoparticle can be used to treat cancer (see first 103 rejection above) (“wherein the cancer is prostate cancer” as in instant claim 175).
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the injection of the first and second therapeutically effective amount is via retro-orbital injection (claim 173).
Wong teaches multistage nanoparticles for deep penetration into tumor tissue (title). IT teaches that Systemic delivery of therapeutics to the tumor is a three-step process: blood-borne delivery to different regions of the tumor, transport across the vessel wall, and passage through the interstitial space to reach the tumor cells (Introduction para 2). Abnormalities in the tumor vasculature lead to highly heterogeneous vascular perfusion throughout the tumor (same para). The microvascular density is high at the invasive edge of the tumor, but sometimes the tumor center is unperfused, preventing delivery of therapeutics to this region (same para). However, the tumor center's hostile microenvironment (low pH and low pO2) harbors the most aggressive tumor cells, and the tumor will regenerate if these cells are not eliminated (same para). Moreover, exposure of the cancer cells to sublethal concentration of the therapeutic agent may facilitate the development of resistance (same para). The reference also teaches the use of initial 100 nm nanoparticles that release 10 nm nanoparticle (Results, para 2). To determine the nanoparticle’s blood half-life to show that the nanoparticles are not rapidly removed from circulation by the reticuloendothelial system, the researchers systemically administered the nanoparticle by retro-orbital injection (Results, para 7). The nanoparticles had a half-life of 22.0 hours, showing that the smaller nanoparticles have a long circulation half-life and deep interstitial penetration required for delivery to the tumor’s poorly accessible regions (same para). This shows that nanoparticles with a size less than 100 nm can be delivered retro-orbitally and renders “wherein the injection of the first and second therapeutically effective amount is via retro-orbital injection” as in instant claim 173 prima facie obvious.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a CAR nanoparticle to treat cancer as taught by Stephan and Jiang, where the administration is via retro-orbital injection as taught by Wong, to arrive at the instantly claimed invention. As Wong shows that a nanoparticle less than 100 nm in size can be administered retro-orbitally, one of ordinary skill would have been motivated to modify the injection method as taught by Stephan and Jiang to include retro-orbital injection with a reasonable expectation of advantageously having the layered nanoparticle have a long circulation half-life and deep interstitial penetration required for delivery to a tumor’s poorly accessible regions as taught by the prior art. This is particularly true for the nanoparticles less than 100 nm in size as taught by Stephan.
Response to Arguments
Applicant has not provided any arguments challenging the specific teachings of cited reference
Wong nor has Applicant attempted to distinguish the instantly claimed invention from what is taught in the prior art reference.
Claim(s) 178 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stephan in view of Jiang et al as applied to claims 148, 150, 152, and 179 above, and further in view of Hirose et al (Br J Cancer. 1995 Sep;72(3):708-14; previously cited).
The teachings of Stephan and Jiang in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 148 of which claim 178 depends. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the cell attractants are selected from CCL3, CCL5, CCL7, CCL8, CCL 3, CCL 1, CCL24, CCL 26, IL-8, or NAP1.
Hirose teaches that chemokine gene transfection reduces tumorigenicity (title). The reference teaches that although the chemokines IP-10 (interferon-inducible protein 10) and MCP-1 (MCAF. JE) (monocyte chemotactic protein 1) have been reported to have potent anti-tumour activity in vivo the other chemokine family members haven’t (p. 708, para 2).
The reference teaches that human interleukin 8, hu-MCP-1 (NICAF), hu-MIP-12 (LD78), murine (mu)-MCP-1 (JE), mu-MIP-lx or mu-MIP-2a were introduced via mammalian expression vectors into Chinese hamster ovary (CHO) cells and the ability of transfected cells to form tumors in vivo was evaluated (abstract). The production of hu-IL-8, hu-MIP-lx or mu-MIP-lx by transfected clones did not influence the growth rate in vitro, but drastically suppressed tumour growth when injected subcutaneously (p. 711, Result; Fig. 3). The reference concludes that IL-8 is a potent chemoattractant for T lymphocytes and an enhanced anti-tumor effects might be expected and that expressing chemokines might provide a synergistic local tumor cell killing (p. 713, para 3 and 7).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a CAR nanoparticle and T cell attractant to treat cancer as taught by Stephan and Jiang in combination, where the T cell attractant is IL-8 as taught by Hirose, to arrive at the instantly claimed invention. As Hirose shows that IL-8 is a potent chemoattractant for T cells, one of ordinary skill would have been motivated to simply substitute one known element [IP-10 T cell attractant of Stephan and Jiang] for another [IL-8 of Hirose] to obtain the predictable result of advantageously having a chemoattractant that drastically suppresses tumor growth.
Response to Arguments
Applicant has not provided any arguments challenging the specific teachings of cited reference
Hirose nor has Applicant attempted to distinguish the instantly claimed invention from what is taught in the prior art reference.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GILLIAN C REGLAS whose telephone number is (571)270-0320. The examiner can normally be reached M-F 7-3.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632