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 .
Claims 1-2, 4-8, 12-13, 15, 17-20, 23, 25, 27, 33, 35 and 40 are pending and examined upon their 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. This application is a 371 national stage entry of PCT/US21/51551 filed on 22 September 2021 that claims domestic benefit to US Provisional Application No. 63/081,699 filed 22 September 2020.
Claims 1-2, 4-8, 12-13, 15, 17-20, 23, 25, 27, 33, 35 and 40 have an earliest effective US filing date of 22 September 2020.
Claim Objections
Claim 13 is objected to because of the following informalities: the claim has a typographical error on line 6, wherein it recites “which is the same or a different as the first polarity”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4-8, 12-13, 15, 17-20, 23, 25, 27, 33, 35 and 40 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 1 is indefinite wherein it recites “performing one or more of” then lists five steps but does not list these in the alternative, rather it recites “and” as the conjunction. It is unclear if steps one through four read as all one step that must be performed together; or, if the claim is meant to be interpreted as written in the alternative. For purposes of applying prior art, the claim will be interpreted as the later – all five steps are recited in the alternative and the claim will be anticipated by “performing one or more” of these steps. This rejection affects the scope of all depending claims.
Additionally, Claim 1 is further indefinite wherein it recites “generating, activating and/or providing for expansion of one or more tumor-reactive T cell and/or cytokine”. When read in light of the specification, it is unclear what processes are encompassed by, for examples, generating a T cell or providing for expansion a cytokine. Absent active method steps, the metes and bounds of processes required for generating, activating and/or providing for expansion are indefinite. For purposes of applying prior art, this will be interpreted as providing a tumor-reactive T cell.
Claim 4 is indefinite wherein it recites “wherein no cytokines…are added”. It is unclear which step within claim 1 this applies to. For example, it is unclear how the steps of “separating activated tumor reactive T cells and/or activated cytokines out” or “inoculating or exposing a patient with/to the …activated cytokines” can be performed wherein no cytokines are added. For purposes of applying prior art, this claim will be interpreted as modifying the only step where this limitation makes sense: “generating, activating and/or providing for expansion of one or mor tumor-reactive T cell, wherein no cytokines or antibodies are added.”
Claim 13, as stated above, has a typographical error that renders the claim indefinite because it recites, “which is the same or a different as the first polarity”. It is unclear what this is referring to and it is inappropriate to import limitations from the specification into the claim.
Claim 15 is indefinite wherein it recites an intended result without any active method steps whereby that result is assessed. The claim states, “exposing the cell sample and the dendritic cells to helper T cells and/or cytotoxic T cells, such that the cytotoxic T cells proliferate” (emphasis added). Yet, there are no active method steps whereby proliferation is assessed. It is unclear if proliferation is or is not required for infringement of the invention of the claim. MPEP 2173.05(g) states: “the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim' and thus be indefinite.” It further states: “Examiners should consider the following factors when examining claims that contain functional language to determine whether the language is ambiguous: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim” (emphasis added). Since the claim fails to meet all (3) criteria set forth in MPEP 2173.05(g), then the scope of Claim 15 is indefinite and the claim is rejected. This affects the scope of all depending claims.
Claim 23 recites the limitation "human" in claims 17/15. There is insufficient antecedent basis for this limitation in the parent claims. In fact, this limitation has been explicitly removed from the parent claims.
Claim 27 is indefinite wherein it recites “a second cell sample or …a second subject”. Claim 27 depends from claims 25 and 15 which only recite a sample. There is insufficient antecedent basis for the limitation of a “second subject” in the claim, therefore the scope of the depending claim is broader than that of the parent claim.
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 1-2, 4-8, 12-13, 15, 17-20, 23, 25, 27, 33, and 40 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 [000123] “lymphocyte expansion and activation in vitro or ex vivo using HFIRE”, does not reasonably provide enablement for the method(s) performed in vivo. 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.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. In addition, when analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be “given their broadest reasonable interpretation consistent with the specification.” See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
As such, the broadest reasonable interpretation of the claimed method is that it provides for in vivo process comprising subjecting the patient to a plurality of electrical pulses. A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification because the disclosure teaches only in vitro or ex vivo methods ([000123] “The present invention demonstrates lymphocyte expansion and activation in vitro or ex vivo using HFIRE. Here, the inventive coculture platform induces CD8+ T cell activation and proliferation by exposure of T cells to HFIRE-treated tumor cells. HFIRE treatment with high voltages and with waveforms with longer pulse durations (5-10 us) induce significant tumor cell death, and can enhance CD8+ T cell proliferation and activation. Activated CD8+ T cells were shown to be cytotoxic to untreated tumor cells. Embodiments of the method of T cell expansion provide an alternative to conventional techniques, and have the unique advantage of not requiring antibodies or cytokines”). The specification goes on to state, “[000118] It is important to keep in mind that T cell activation is a complex process with many factors playing into its dynamics”. The complexity only increases when this process is induced in vivo. Figure 8 of the disclosure provides an exemplary schematic of the process in vivo, there is no actual reduction to practice of this embodiment. The specification only describes an in vitro or ex vivo method depicted in the Inventors’ post-filing article, inserted below (NPL cite no. 2 on the IDS filed 03/22/2023), and this is the only method whereby “separating activated tumor-reactive T cells and/or activated cytokines out” (claim 1, second to last step) and the step of inoculating a patient with said cells (claim 1, last step), can feasibly be performed.
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Regarding the in vivo use of high-frequency irreversible electroporation (H-FIRE), the following prior art disclosed H-FIRE is a feasible technique for non-thermal tissue ablation that eliminates muscle contractions seen in IRE treatments performed with unipolar electric pulses, and has the potential to be performed clinically without the administration of paralytic agents. However, there was nothing within the art that taught in vivo H-FIRE simultaneously with in vivo immunotherapy comprising inoculation with activated tumor-reactive T cells, as claimed.
Thus, what is enabled by the working examples is narrow in comparison to the breadth of the claims. The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentech, Inc, v. Novo Nordisk, 42 USPQ 2d 1001, (CAFC 1997), the court held that:
"[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" and that "[t]ossing out the mere germ of an idea does not constitute enabling disclosure". The court further stated that "when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art", "[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement".
The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is in vivo electroporation, a person having ordinary skill in the art would have to perform multiple further in vivo experiments, in animal models that are predictive of Adoptive cell transfer (ACT) for cancer immunotherapy, in order to demonstrate use of the method in vivo with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine’ within the art, and constitutes undue further experimentation.
Therefore, Claims 1-2, 4-8, 12-13, 15, 17-20, 23, 25, 27, 33, and 40 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Claim Rejections - 35 USC § 102
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 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.
Claims 1-2, 4-8, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Neal et al., PLoS One 8(5): e64559, 2013.
Regarding claim 1, Neal et al. teach a method comprising: subjecting one or more patient cell (e.g., tumor cells) to a plurality of electrical pulses, wherein the subjecting is performed in vivo. Specifically, Neal et al. teach methods of irreversible electroporation (IRE) comprising: pulse delivery plate electrodes were placed on opposing sides of a tumor that was implanted into mice in vivo (see Fig. 1). Electric pulses were delivered between the plates with a voltage-to distance ratio of 1500 V/cm, each 100 ms long, delivered at a rate of 1 pulse per second. A total of 100 pulses were delivered, reversing polarity after the first 50. Following pulse delivery, the electrodes and needles were reoriented 90o, and the pulsing process was repeated, delivering a total of 200 pulses to the tumor (pg. 4, paragraph bridging columns). Further, the prior art teaches subsequent to IRE changes to immune markers were observed from tumors treated with IRE in immunocompetent rats, including changes in CD4 +/CD8+ ratio, cytokine IFN-γ and IL-10 (pg. 2, paragraph bridging columns). Thus, the prior art teaches generating, activating and/or providing for expansion of one or more tumor-reactive T cells, such as CD4+ cells and/or CD8+ cells, and/or cytokines. Lastly, the prior art discloses: “Further, in addition to evidence for IRE-induced tumor cell apoptosis, the evidence for IRE to cause immediate necrosis of the ablated region may present the body’s immune system with all three signals required to incite a tumor-specific adaptive immune response. IRE ablation promotes near-immediate edema and an inflammatory response, rapidly attracting lymphocytes to the treated region” (pg. 8, second column, third full paragraph) and “With necrosis, there is significant release of intracellular contents, such as pro-inflammatory cytokines” (pg. 8, fourth paragraph). Thus, the prior art teaches IRE ablation provides for “activating … of one or more tumor-reactive T cells and/or cytokines”, as claimed.
Regarding claim 2, the prior art teaches pulse delivery plate electrodes were placed on opposing sides of a tumor that was implanted into mice in vivo, which teaches “positioning one or more electrodes near a target area containing cells to be treated; applying a plurality of electrical pulses to the target area through the electrodes,” as recited by the claim. Further, Neal et al. teach, “Several studies have demonstrated that necrotic cells will lead to increased dendritic cell (DC) and macrophage activation [38,39]” (pg. 8, fourth paragraph). Thus, the IRE protocol leads to “exposing treated cells to dendritic cells; and exposing the treated cells to one or more types of T lymphocytes,” as claimed.
Regarding claim 4, while the reference disclose further studies combine electroporation with “cytokine encoding plasmids” (pg. 2, third paragraph), however, the IRE method of Neal et al. does not require the adjunct administration of antibodies or cytokines.
Regarding claim 5, the plurality of electrical pulses are administered at a voltage in the range of above 0 V to 10,000 V, wherein it discloses, “Electric field exposure within the tumor of the treatment groups had median and quartile (1st/3rd) ranges of 839 V/cm (749/1185 V/cm) for the IC treated mice and 838 V/cm (479/1055 V/cm) for the ID mice, showing similar tumor exposure to IRE despite the clipped fur on the skin of IC mice” (pg. 5, Results, first paragraph).
Regarding claim 6, the Neal et al. prior art teaches pulses of the plurality have duration of 100 ms long, which is outside the range of the claim, which states “from about 1 picosecond to 50 microseconds”. The Court has stated that, generally, such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421. MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical because paragraph [00051] of the disclosure states a “pulse width and intra-phase delay ranging from 0.1 µs to 10 ms and an inter-pulse delay ranging from 0.1 µs to 1 s .” Therefore, there appears to be no criticality that the pulse width is the about 1 picosecond to 50 microseconds of the instant claim.
Regarding claim 7, the Neal et al. prior art discloses, “A total of 100 pulses were delivered, reversing polarity after the first 50” (pg. 4, paragraph bridging columns). The specification discloses these as bipolar pulses (see [00080]). Thus, the prior art discloses a positive pulse-delay-negative pulse protocol or negative pulse-delay-positive pulse protocol, as claimed.
Regarding claim 8, the Neal et al. prior art discloses pulses “delivered at a rate of 1 pulse per second” (pg. 4, paragraph bridging columns), which is the equivalent to 1 Hz. This falls squarely within the claimed range of above 0 Hz to 100 MHz.
Regarding claim 12, since the Neal prior art teaches pulses delivered at a rate of 1 pulse per second, with a pulse duration of 100 ms, then there is necessarily an inter-pulse delay of 900 ms since there are 1000 milliseconds in one second.
Therefore, the invention of the claims fails to distinguish over the methods disclosed in the prior art.
Claims 15, 17-20, 23, 25, 27, and 35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhao et al., Nature Communications, 10: 899, 2019 (NPL Cite No. 4 on the IDS filed 03/22/2023), as evidenced by Manuel et al., Cancer Immunology Res., 3(9):1096-1107, 2015.
Regarding claim 15, the Zhao et al. prior art teaches methods comprising in vitro cultures of tumor cells to investigate the mechanisms underlying the durable responses by [irreversible electroporation] IRE (Figure 8 and pg. 7 first two paragraphs). The Figure 8 legend utilizes tumor cells “suspended in phosphate buffered saline”. The legend specifically recites, “ Cells were analyzed within 30 min of treatments. d Representative expression of [dendritic cell] DC activation markers, including CD40, MHC-II, CCR7, and CD86, on bone marrow-derived DCs (CD11c+) after incubation with KRAS* cells for 24 h.” Further, the figure analyzes the number of CD8+ T cells and T reg cells following IRE. Therefore, the prior art teaches applying a plurality of electrical pulses to a cell sample in vitro or ex vivo, culturing the sample with dendritic cells, and exposing the sample and dendritic cells to helper T cells and/or cytotoxic T cells. Lastly, the prior art discloses isolating cytotoxic T cells from samples by flow cytometry (Figure 4C).
Regarding claim 17, the Zhao reference discloses isolating CD8+ cytotoxic T cells and analyzing the number of CD8+ T cells and T reg cells following IRE (Figures 4 and 8).
Regarding claim 18, the Zhao reference discloses isolating CD4+ and CD8+ T cells from splenocytes (Figure 4c), thus teaching “isolated from an organ,” as claimed.
Regarding claim 19, the Zhao et al. reference discusses immunotherapies throughout (Abstract; pg. 2, third paragraph; pg. 5, paragraph bridging columns; pg. 10, last paragraph; and, pg. 12, paragraph bridging columns). Therefore, the prior art discloses methods comprising administering CD8+ T cells to a patient were well-established in the art prior to filing.
Regarding claim 20, the Zhao et al. prior art disclose a Salmonella-based immunotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC) (pg. 12, first sentence), wherein it references the Manuel prior art. The Manuel et al. reference is relied upon solely as evidence that this in vitro/ex vivo method comprises exposing tumor cells to CD8+ T cells from shIDO-ST treated splenocytes, in combination with the HA-depleting agent PEGPH20. This combined therapy helps the CD8+ T cells infiltrate solid pancreatic tumors. Thus, the prior art discloses methods comprising exposing CD8+ cells to a second cell sample, namely crude splenocytes from mice bearing tumors and having been exposed to shIDO-ST. In this way the prior art teaches further comprising exposing isolated CD8+ cells to a second cell sample from an individual that is different from the first cell sample.
Regarding claim 23, as stated above, following IRE the Zhao prior art analyze the content of cells within the tumor ex vivo. Figure 4 of the reference teaches expression of [dendritic cell] DC activation markers, including CD40, MHC-II, CCR7, and CD86. Thus, the prior art teaches exposing the cell sample and dendritic cells to antibodies. The Zhao et al. reference further discloses that this is a common course of chemotherapy wherein it recites, “Concomitant treatment with antibody to cytotoxic T lymphocyte-associated antigen-4 (anti-CTLA4) and anti-PD1 was previously reported to generate a rapid and strong tumor regression in melanoma patients” (pg. 2, second to last paragraph). Also, the prior art utilizes CD8-neutralizing antibody for depletion studies (pg. 4, last paragraph). Thus, the prior art teaches exposing sample and dendritic cells to antibodies.
Regarding claim 25, Zhao et al. disclose the cell sample is obtained from a first subject, namely, a mouse orthotopic PDAC model (a.k.a KRAS* model) (pg. 2, Results, first paragraph).
Regarding claim 27, while the method of Zhao et al. does not isolate CD8+ cells and administer these to a second sample or individual, as stated above, the prior art discusses immunotherapies in the form of adoptive cell transfer, throughout. Therefore, the prior art teaches these methods were known in the art prior to filing, and the experiments of Zhao are aimed at improving immunotherapy methods, which are often unsuccessful in treating solid pancreatic tumors (Abstract).
Regarding claim 33, Zhao and colleagues teach applying a plurality of pulses to a mouse KRAS* model in vivo. Isolating one or more cells, namely tumor cells, and culturing those with bone marrow dendritic cells (Figure 5). Further, Figure 3 of the reference demonstrates that this in vivo model yields intra-tumoral cells comprising tumor cells, cytotoxic CD8+ cells and dendritic cells (DC). Therefore the prior art teaches exposing the one or more tumor cells to dendritic cells and T cells and isolation of the cytotoxic CD8+ T cells by frow cytometry.
Regarding claim 35, the method of Zhao comprises applying a plurality of pulses to a cell sample, namely a tumor, in vitro/ex vivo (Figure 3) and isolating said tumor cells (“isolating one or more of the cells of the subject). The prior art further teaches: “To investigate whether IRE-treated KRAS* cells mediated activation and maturation of DCs …cells were incubated with bone marrow-derived murine dendritic cells (DCs) for 24 h. Flow cytometry analyses (Fig. 5c) showed that IRE-treated KRAS* cells increased the expression of DC activation/maturation markers CD40, CCR7, and CD86 by 72 ± 2%, 52 ± 4%, and 51 ± 4% (mean ± SEM, n = 3), respectively, compared to live KRAS* cells, in the tumor cell-exposed DCs (p < 0.01, two-sided Student’s t-test)” (pg. 5, second paragraph). Thus, the prior art teaches culturing the one or more cells (tumor cells) with dendritic cells, as claimed.
Thus, the methods of the invention fails to distinguish over methods disclosed in the prior art references.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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 13 is rejected under 35 U.S.C. 103 as being unpatentable over Neal et al. as applied to claims 1-2, 4-8, and 12 above, and further in view of Sano et al. Scientific Reports, 5: 14999, 2015.
The teachings of Neal, as they pertain to Claims 1-2, 4-8, and 12, are outlined in the rejection under 102 above. Neal teaches dual polarity pulses the are 100 ms in duration with a delay of 900 ms in between pulses that are delivered every 1 second.
Neal is silent with respect to the specific pulsing scheme of instant claim 13:
administering a pulse with a first polarity and a pulse duration of less than 10 microseconds,
administering a delay with a duration of up to 20 microseconds
administering a pulse with a second polarity, which is the same or a different [voltage] as the first polarity, and a pulse duration of less than 10 microseconds,
administering a delay of up to 1 second, and
repeating the administering of (i)-(iv) a desired number of times.
The Sano et al. prior art reference, however, teaches a similar in vivo irreversible electroporation protocol, as taught by Neal et al., but with a shorter pulse duration. Sano et al. discloses methods by Arena et al. that demonstrate in vivo H-FIRE treatments with 1 or 2 microsecond pulsed (pg. 2, third full paragraph). Sano et al. state, “pulses in the 1 to 100μs range are still relatively unexplored.” The specific methodology used by Sano et al. comprises “lethal electric field intensity increased from 530V/cm to 2020V/cm as the pulse-width was decreased from 50μs to 250ns, respectively. We showed that H-FIRE was effective in vivo against a murine flank tumor model using bursts containing 1, 2, and 5μs pulses” (pg. 2, fifth full paragraph). Figure 1 show the specific protocol used by Sano comprising high frequency bipolar pulses with a 2 microsecond delay between positive and negative pulses that are themselves 2 microseconds in duration. The Figure legend teaches “eighty bursts containing (D) 2, (E) 24, and (F) 50 bipolar 2μs pulses with a 2μs delay between alternating pulses”. Figure 1B demonstrates 1 second delay between bursts and Table 1 of the reference depicts all of the different parameters used. The method of Sano et al. teaches all of the elements of the claim: bipolar pulses with a duration of less than 10 microseconds, repeatedly administered with a delay of up to 1 second in between bursts.
It would have been obvious to a person having ordinary skill in the art, before the effective filing date of the application, to use the protocol as taught by Sano et al. in place of the protocol as taught by Neal. Motivation to use the Sano protocol is explicit within the reference wherein it demonstrates the shorter duration pulses are effective at killing cells (Figure 1, red cell staining) and Figure 4 of Sano et al. demonstrates successful inhibition of tumor growth. Further motivation is explicit wherein the Sano reference teaches this shorter protocol reduces muscle contractions in vivo (pg. 8, third and fourth paragraphs), whereas 100 microsecond pulses require complete anesthesia. A person having ordinary skill would have been able to use the Sano protocol with predictable success since the Sano reference teaches successful induction of cell death with shorter duration pulses, and Neal teaches that it was well-established in the prior art that immediate necrosis of the ablated region may present the body’s immune system to incite a tumor-specific adaptive immune response; necrosis leads to significant release of pro-inflammatory cytokines; and, will lead to increased dendritic cell (DC) and macrophage activation.
Therefore, the method of the prior art is obvious in view of the teachings of the prior art references.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. as evidenced by Manuel et al. as applied to claims 15, 17-20, 23, 25, 27, and 35 above, and further in view of the MACS Miltenyi Biotec brochure (2019).
The teachings of Zhao et al. in view of Manuel, as they pertain to the limitations of claims 15, 17-20, 23, 25, 27, and 35 are outlined in the rejection under 102 above.
While the method of Zhao utilizes flow cytometry cell sorting, and specifically BD FACSCalibur (pg. 12, Methods, Electroporation) to isolate CD8+ cytotoxic T cells following IRE (Figure 3b), it does not disclose magnetic-activated cell sorting, recited by instant claim 40.
The MACS Miltenyi Biotec brochure (2019), however, remedies this deficiency by disclosing methods for the generation of functional CAR T cells from the CD8+ T cells were known in the art prior to filing. Specifically, the MACS brochure discloses CD8+ MicroBeads and the autoMACS® Pro Separator can be used to isolate T cells from a cell sample and then can be transduced with the CD19 CAR construct (pg. 1 Method). The method results in >98% purity (Figure 1B).
It would have been obvious to a person having ordinary skill, before the effective filing date of the application, that the MACS magnetic cell sorting could be substituted for the FACSCalibur method disclosed in Zhao. An artisan having ordinary skill in the cancer arts would have recognized that this substitution would predictably result in isolation of a relatively pure population of CD8+ T cells that can then be transduced to express a chimeric antigen receptor against CD19. Motivation to use the MACS system, according to known methods, is explicit wherein it teaches CD8+ cells isolated and transduced result in approximately 80% killing of target tumor cells (GFP+CD19+ JeKo-1) when used at a 5-fold excess of CD19-directed CAR T cells (Fig. 3).
Therefore, the method of the invention is obvious in view of what was known and disclosed in the art prior to filing.
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.
Claims 1-2, 4-8, 12-13, 15, 17-20, 23, 25, 27, 33, 35 and 40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 7-8, 10, 14 16, 20, 36, 42, 45, 48-49, 51-53, 59, 61 and 64 of copending Application No. 18/846,198 (reference application) in view of Neal et al., cited above.
Although the claims at issue are not identical, they are not patentably distinct from each other because all of the independent claims in the instant application recite subjecting one or more cells to a plurality of electrical pulses performed in vitro, in vivo, or ex vivo. The reference claims treating tissue with electrical pulses comprising: administering one or more or a plurality of electrical pulses to cells of a target tissue according to a pulsing protocol expected to achieve a desired cell death gradient based on one or more cell death mechanism chosen from apoptosis, pyroptosis and/or necroptosis. The limitation “to achieve a desired cell death gradient based on one or more cell death mechanism chosen from apoptosis, pyroptosis and/or necroptosis” is merely an intended result that occurs subsequent to the active step of administering a plurality of electrical pulses to cells of a target tissue according to a pulsing protocol. The Neal prior art teaches there is evidence irreversible electroporation (in which electrical pulses are delivered to cells of a target tissue, namely tumor tissue) results in apoptosis and necrosis (aka necroptosis; see pg. 8, paragraph bridging columns). Therefore, the method of the instant claims anticipates the method of the pending reference claims, particularly in view of what was known in the prior art pertaining to the cell death mechanisms that inherently result from IRE or HFIRE.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STACEY NEE MACFARLANE whose telephone number is (571)270-3057. The examiner can normally be reached M-F 7:30-5 (EST) & Sat. A.M..
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/STACEY N MACFARLANE/ Examiner, Art Unit 1675
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