DETAILED ACTION
Status of the Claims
Claims 1, 3, 6-14, 16-21 and 26-28 are pending in the instant application and are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 03/30/2020, the filing date of the priority document GB2004629.8.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17 remains 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 pre-AIA the applicant regards as the invention.
Claim 17 recites the limitation "said cancer" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Particularly, claim 1 recites “cancer or metastatic cancer” (line 2) which should be similarly referenced as limiting the child claim 17. Appropriate clarification is required.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3-9, 14, 16-18, 21, 27 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over CARPENTER (US 2003/0044354) in view of Chen et al. (“Ultrasound-targeted microbubble destruction for chemotherapeutic drug delivery to solid tumors,” 2013; Journal of Therapeutic Ultrasound Vol. 1, No. 10, pp. 1-8); BAYEVER (US 2016/0375004; published December, 2016) and Suker et al. (“FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis,” 2016, The Lancet Oncology, Vol. 17, No. 6, pp. 801-810).
Applicants Claims
Applicant claims a method of treating cancer in a patient in need thereof, said method comprising the steps of: (1) administering to affected cells or tissues of said patient an effective amount of a microbubble-chemotherapeutic complex which comprises a microbubble carrying a combination of chemotherapeutic agents, wherein said combination of chemotherapeutic agents comprises: (a) a 5-fluoropyrimidine or a derivative thereof; (b) irinotecan or a derivative thereof; and (c) a platinum-based chemotherapeutic agent or derivative thereof; (2) simultaneously, separately or sequentially administering to said patient an effective amount of folinic acid or a derivative thereof; and subjecting said cells or tissues to ultrasound irradiation whereby to rupture said microbubble (instant claim 1). Applicant claims the 5-fluoropyrimidine or a derivative thereof includes 5-fluorouracil (5-FU)(instant claim 2); the irinotecan [is] in the form of its free base (claim 3); the platinum-based chemotherapeutic agent is oxaliplatin (instant claims 4-5).
Determination of the scope
and content of the prior art (MPEP 2141.01)
CARPENTER teaches gas microsphere liposome composites for ultrasound imaging and ultrasound stimulated drug release (title, see whole document), and particularly “Formulations comprising a gas microsphere liposome composite suspended in a medium, wherein the gas microsphere liposome composite comprises: a gas-filled microsphere; at least one of a lipid and a surfactant adsorbed onto the surface of the gas-filled microsphere; and liquid-filled liposomes attached to the lipid or surfactant are described. Methods of preparing the same and using them in ultrasound imaging are also described. The present invention also comprises use of the same in treating heart disease, inflammation, infection, cancer or thromboembolic disease in a patient.” [emphasis added](abstract)(instant claim 16).
CARPENTER teaches that: “The present invention provides a formulation for contrast enhancement of ultrasound imaging and for ultrasound (i.e., acoustically) stimulated drug release. The formulation provides stable gas microsphere (i.e., finely divided gas bubbles) suspensions with excellent and stable acoustic response properties when in dilute aqueous suspensions. The formulation can deliver a higher level of active drug per gas-filled microsphere to a given tissue, relative to known formulations, thereby achieving the intended therapeutic benefit of high local concentrations of drug or gene in the region of pathology.” ([0026]). And particularly that: “The method includes administering to the patient (e.g., mammal) an effective amount of a formulation of the present invention, wherein one or more of the liquid-filled liposomes independently includes a therapeutic agent; allowing a sufficient period of time for the circulation of the gas microsphere composite to the targeted area; and applying ultrasound energy to the targeted area in the patient (e.g., mammal) sufficient to cause the therapeutic agent to be released from the microsphere liposome composite at the region of pathology.” ([0029])(instant claim 1, a method of treating cancer comprising administering to affected cells or tissues of said patient an effective amount of a microbubble-chemotherapeutic agent”).
CARPENTER teaches that: “As illustrated in FIG. 2 and FIG. 3, the gas microsphere liposome composite (1) (MSLC) includes liquid- filled liposomes (7) (LFLs) attached to the lipid (5) or surfactant ( 6). The presence of liquid-filled liposomes (7) stabilizes the surfactant-encapsulated or lipid-encapsulated gas-filled microsphere (3).” ([0059]). And further that: “As illustrated in FIG. 2 and FIG. 3, one or more of the LFLs (7) may include one or more suitable drugs (e.g., therapeutic agents (9) and/or diagnostic agents (9)) in the liquid-filled internal volume. Each of the liquid-filled liposomes (7) may independently include one or more drugs (e.g., therapeutic agents (8) and/or diagnostic agents (9)) in the liquid interior (10) of the liquid-filled liposomes (7). The LFLs (7), when attached to the surfactant-coated or lipid-coated gas-filled microsphere (3) surface, can be burst upon ultrasound stimulation and release the one or more therapeutic drugs (e.g., therapeutic agents (8)) in a diseased organ or tissue in a localized and concentrated fashion. High energy ultrasound is generally capable of causing the gas-filled microsphere (3) to expand and contract rapidly, which eventually leads to gas bubble rupture. The ultrasound energy captured by the gas-filled microsphere (3) will cause the MSLC (1) to fragment and rupture, in turn, releasing the one or more drugs (e.g., therapeutic agents (8)) contained in the interior of the LFLs (7) attached to the surface of the MSLC (1).” ([0064])(instant claim 1, “ subjecting said cells or tissues to ultrasound irradiation whereby to rupture said microbubble”). And teaches various antineoplastic agents (chemotherapeutic agents) including doxorubicin, methotrexate, gemcitabine, and cisplatin (a platinum-based chemotherapeutic agent), among others ([0065]).
CARPENTER teaches that: “Additionally, the gas-filled microsphere (3) typically has an average diameter of about 0. 1 µm to about 10 µm.” ([0050]), and that: “The gas microsphere liposome composite (1) (MSLC) can exist as an aggregate of two or more gas microsphere liposome composites (1). The aggregate will typically have a diameter of about 1 µm to about 100 µm.” ([0053])(instant claim 6).
CARPENTER teaches that: “The gas-filled microsphere (3) will typically include one or more suitable inert gases ( 4). Suitable inert gases ( 4) of the present invention are well known in the field of ultrasound contrast agents. […] Suitable inert gases ( 4) useful in the present invention include, e.g., perfluorocarbon gases (e.g. (C2 -C6) perfluorocarbons), perfluoroether gases, Nitrogen, and noble gases (e.g., Helium, Argon, and Neon).” ([0051]). CARPENTER teaches the use of perfluoropropane ([0099], [0114]) and perfluorobutane ([0129], [0133])(instant claim 7).
CARPENTER teaches that: “For targeted delivery of one or more drugs (e.g., therapeutic agents (8) and/or diagnostic agents (9)) to a selected pathological condition, the LFLs (7) of the present invention can be derivatized with a high affinity, targeting moiety (11) that is covalently linked or adsorbed onto the surface (13) of the LFLs (7). […] This is accomplished by providing ligands on the LFLs (7) that have high affinity for receptors, enzymes, mRNA, or DNA which are over-expressed or altered in dysfunctional cells at sites of diseases.” ([0068]). And “Suitable specific targeting moieties (11) include, e.g., […] DPPE-PEG3400” ([0070], also see , [0023])(instant claim 8).
CARPENTER teaches that: “The present invention provides a formulation that includes a gas microsphere liposome composite (MSLC) suspended in a medium. The gas microsphere liposome composite includes a gas-filled microsphere; at least one of a lipid and a surfactant adsorbed onto the surface of the gas-filled microsphere; and liquid-filled liposomes attached to the lipid or surfactant.” ([0027])(instant claim 9).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of CALLAN is that CALLAN does not expressly teach simultaneously, separately or sequentially administering to said patient an effective amount of folinic acid (instant claim 1); or the chemotherapeutic agents are incorporated into the shell of the microbubble (instant claim 14).
Chen et al. teaches that: “Ultrasound-targeted microbubble destruction (UTMD) is a promising technique for non-invasive, targeted drug delivery, and its applications in chemotherapeutic drug delivery to solid tumors have attracted growing interest. Ultrasound, which has been conventionally used for diagnostic imaging, has evolved as a promising tool for therapeutic applications mainly because of its ability to be focused deep inside the human body, providing a modality for targeted delivery. Although originally being introduced into clinics as ultrasound contrast agents, microbubbles (MBs) have been developed as a diagnostic and therapeutic agent that can both be tracked through non-invasive imaging and deliver therapeutic agents selectively at ultrasound targeted locations. Whereas free drugs often possess harmful side effects, their encapsulation in MBs and subsequent local release at the targeted tissue by ultrasound triggering may help improve the margin of safety.” (abstract, see whole document). One of ordinary skill would have recognized that directly delivering microparticle-drug complexes to cancer cells or tissues would have reduced the dose needed because local delivery of the drug to the site of action reduces the amount relative to systemic delivery therefore reasonably implying a subtherapeutic dose (instant claims 18 & 28)(MPEP §2144.01).
Chen et al. teaches that: “MBs, bubbles with diameters of less than 10 μm, are made of a phospholipid, surfactant, albumin, or synthetic polymer shell filled with high molecular weight gas with a very low water solubility (e.g., sulfurhexafluoride or perfluorepropane gas). Bioactive substances (e.g., genes, drugs, proteins, and gene silencing constructs) can be attached to or incorporated in the MBs.” [emphasis added](p. 1, col. 2, last paragraph)(instant claim 14).
BAYEVER teaches treatment of pancreatic cancer “in a patient by administering liposomal irinotecan (MM-398) alone or in combination with additional therapeutic agents. In one embodiment, the liposomal irinotecan (MM-398) is co-administered with 5-fluorouracil and leucovorin.” [emphasis added](title, abstract, see whole document). BAYEVER teaches that: “Leucovorin (also called folinic acid) acts as a biochemical cofactor for 1-carbon transfer reactions in the synthesis of purines and pyrimidines. Leucovorin does not require the enzyme dihydrofolate reductase (DHFR) for conversion to tetrahydrofolic acid. The effects of methotrexate and other DHFR-antagonists are inhibited by leucovorin. Leucovorin can potentiate the cytotoxic effects of fluorinated pyrimidines (i.e., 5-fluorouracil and floxuridine). After 5-FU is activated within the cell, it is accompanied by a folate cofactor, and inhibits the enzyme thymidylate synthetase, thus inhibiting pyrimidine synthesis. Leucovorin increases the folate pool, thereby increasing the binding of folate cofactor and active 5-FU with thymidylate synthetase.” [emphasis added]([0107]).
BAYEVER teaches that: “Liposomal irinotecan is administered intravenously, either alone or in combination with 5-fluorouracil (5-FU) and/or leucovorin. In one embodiment, liposomal irinotecan is administered prior to 5-FU and leucovorin. In another embodiment, leucovorin is administered prior to 5-FU.” ([0111])(instant claim 1, “sequentially administering […] folinic acid.”).
Regarding instant claim 21, BAYEVER teaches that: “Single-agent gemcitabine is the current standard of care in first-line treatment of advanced and metastatic pancreatic adenocarcinoma. […] Single agent gemcitabine was also approved as second line treatment for patients previously treated with but no longer responsive to 5-fluorouracil, with a median overall prolongation of survival of 3.9 months.” [emphasis added]([0006])(instant claims 16 & 27). Therefore, it is clearly prima facie obvious to utilize a drug combination as a second line of treatment, particularly in patients no longer responsive to a first line treatment.
Suker et al. teaches that “Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population.” [emphasis added](p. 801, Summary – Background)(instant claim 1, items (a), (b), (c) and folinic acid). Suker et al. teaches that: “The regular FOLFIRINOX regimen, as described in the PRODIGE 4 trial,9 consisted of a 2-h intravenous infusion of oxaliplatin (85 mg/m²) followed by a 2-h intravenous infusion of leucovorin (400 mg/m²) concomitantly with a 90-min intravenous infusion of irinotecan (180 mg/m²), followed by a bolus (400 mg/m²) and a 46-h continuous infusion (2400 mg/m²) of fluorouracil.” (p. 802, col. 2, lines 11-15). Suker et al. teaches that the 3 patient studies were rejected because the were “investigated FOLFIRINOX not first-line therapy” (instant claim 21).
Suker et al. teaches that: “Palliative gemcitabine has been the standard of care for patients with locally advanced pancreatic cancer for more than a decade, with a modest survival benefit of about 3 months compared with best supportive care. In patients with metastatic pancreatic cancer, FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) was shown to improve the median overall survival compared with gemcitabine (11 months vs 7 months). In the past few years, several studies have assessed FOLFIRINOX for locally advanced pancreatic disease.”(p. 802, box at top, §Evidence before this study). And that: “Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months—longer than that reported with gemcitabine (6–13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX.” (p. 801, §Interpretation).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a method for the treatment of pancreatic cancer by ultrasound microbubbles carrying a combination of chemotherapeutic agents, and particularly 5-FU, irinotecan and oxaliplatin with administration of folinic acid (leucovorin) which combination was known as FOLFIRINOX, as this drug combination is clearly suggested by the prior art as effective for the treatment of pancreatic cancer, CARPENTER teaching microbubbles for the treatment of cancer, and BAYEVER and Suker et al. suggest this combination of drugs, and the administration of folinic acid with 5-FU is also the combination of drugs being attached to the microbubbles, as suggested by CARPENTER, or alternatively incorporated into the microbubbles shell, as suggested by Chen et al., and particularly given that Suker et al. teaches improved survival of FOLFIRINOX patients vs. gemcitabine (standard of care for patients with locally advanced pancreatic cancer).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because the utility of microbubbles for delivery of anticancer agents was known prior to the time of the claimed invention, and it would have been within the ordinary level of skill in the art to produce and administer the same to pancreatic cancer patients. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Claims 10-13 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over CARPENTER in view of Chen et al.; BAYEVER and Suker et al. as applied to claims 1, 3-9, 14, 16-18, 21, 27 and 28 above, and further in view of CALLAN (WO 2018/220376 A1; published December, 2018; of record as cited by Applicant on 01/17/2023).
Applicants Claims
Applicant claims a method of treating cancer in a patient in need thereof, said method comprising the steps of: (1) administering to affected cells or tissues of said patient an effective amount of a microbubble-chemotherapeutic complex which comprises a microbubble carrying a combination of chemotherapeutic agents, as discussed above. Applicant further claims the platinum-based chemotherapeutic agent or derivative thereof is attached to the microbubble via a biotin-avidin interaction (claim 10), the one or more of said combination of chemotherapeutic agents are attached to the microbubble via a covalent linkage (claim 11) including said 5-fluoropyrimidine or derivative thereof and/or platinum-based chemotherapeutic agent is/are attached to the microbubble via a covalent linkage (instant claim 12-13). Applicant further claims the irinotecan is incorporated into the shell of the microbubble (instant claim 26).
Determination of the scope
and content of the prior art (MPEP 2141.01)
CARPENTER teaches a microsphere-antineoplastic agent composite for drug delivery using ultrasonic energy to rupture and release the drug(s), as discussed above and incorporated herein by reference.
Chen et al. teaches microbubbles for delivery of chemotherapeutic drugs to solid tumors, as discussed above and incorporated herein by reference.
BAYEVER teaches treatment of pancreatic cancer by a liposomal formulation of irinotecan, 5-FU and folinic acid, as discussed above and incorporated herein by reference.
Suker et al. teaches that “Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population.”, as discussed above and incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of CARPENTER et al. is that CARPENTER et al. do not expressly teach the covalent linkage of one or more of the therapeutic agents to the microsphere (microbubble) including biotin-avidin-biotin interaction (instant claims 1-13), or the irinotecan is incorporated into the shell of the microbubble (instant claim 26).
CALLAN teaches “The invention relates to microbubble complexes for use in methods of sonodynamic therapy which comprise a microbubble attached to or otherwise associated with one or more linking groups, each linking group being bound to at least one sonosensitising agent and at least one chemotherapeutic agent. It further relates to the micro bubble complexes themselves and to pharmaceutical compositions which contain them. The invention is particularly suitable for the treatment of deep-sited tumors, in particular pancreatic cancer.”(abstract, see whole document).
CALLAN teaches that: “In one embodiment the interaction between the linking group(s) and the microbubble may involve strong non-covalent bonding such as the biotin-avidin interaction. In this embodiment one component of the binding pair (e.g. the linking group) is functionalised with biotin and the other (e.g. the microbubble) with avidin. Since avidin contains multiple binding sites for biotin, this will typically also be bound to the microbubble via a biotin-avidin interaction.” (p. 7, last paragraph; p. 32, last paragraph)(instant claim 10).
CALLAN teaches that: “Where the microbubble is bound to more than one chemotherapeutic agent, these may be the same or different, and may be carried by a single linking group or two or more linking groups. Generally, the chemotherapeutic agents attached to a particular microbubble via a linking group (or groups) as herein described will be identical.” (p. 7, 4th paragraph). And that: “The chemotherapeutic agent(s) and sonosensitising agent(s) are linked to the microbubble via one or more linking groups. Each linking group may be bound to or otherwise associated with the microbubble and the chemotherapeutic agent(s) and sonosensitising agent(s) through covalent or non-covalent means, e.g. via electrostatic interaction, hydrophobic interactions, van der Waals forces, hydrogen bonding, or any combination thereof.” (p. 7, 5th paragraph). CALLAN further teaches that: “In one embodiment, the chemotherapeutic agent(s) and/or sonosensitising agent(s) are covalently bound to the linking group(s), i.e. the chemotherapeutic agent(s) and/or sonosensitising agent(s) are attached to the linking group(s) via one or more covalent bonds.” (instant claims 11-13). CALLAN further teaches that: “The microbubble complexes herein described may be prepared using methods and procedures known in the art. Methods which may be used for covalently attaching the chemotherapeutic agent and/or the sonosensitising agent to a linking group include known chemical coupling techniques.” (p. 31, 3rd paragraph).
CALLAN teaches that: “As an alternative to coupling of the linking group to a pre-formed microbubble, this may alternatively be linked to a lipid (e.g. using any of the methods described above) and that lipid may subsequently be incorporated into the lipid shell of the microbubble during its preparation.” (p. 32, 3rd paragraph). And that: “Methods for the preparation of a microbubble-sonosensitiser complex or a microbubble-chemotherapeutic agent complex having a chemotherapeutic agent embedded within the shell of the micro bubble which comprise the step of incorporating a chemotherapeutic agent into the microbubble shell, for example using any of the techniques herein described, form a further aspect of the invention.” (p. 40, 2nd paragraph). CALLAN teaches topoisomerase I inhibitors, particularly irinotecan (claim 16), and “A complex as claimed in any one of the preceding claims, wherein the micro bubble comprises a shell having incorporated therein one or more additional chemotherapeutic agents.” (claim 18). It would have been prima facie obvious to incorporate any of the chemotherapeutic agents into the shell of the microsphere per the teachings disclosure of CALLAN (instant claim 26).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a method for the treatment of pancreatic cancer by ultrasound microbubbles carrying a combination of chemotherapeutic agents, and particularly 5-FU, irinotecan and oxaliplatin with administration of folinic acid (leucovorin) which combination was known as FOLFIRINOX, as this drug combination is clearly suggested by the prior art as effective for the treatment of pancreatic cancer, CARPENTER teaching microbubbles for the treatment of cancer, and BAYEVER and Suker et al. suggest this combination of drugs, and the administration of folinic acid with 5-FU is also the combination of drugs being attached to the microbubbles, as suggested by CARPENTER, or alternatively incorporated into the microbubbles shell, as suggested by Chen et al., and particularly given that Suker et al. teaches improved survival of FOLFIRINOX patients vs. gemcitabine (standard of care for patients with locally advanced pancreatic cancer), the chemotherapeutic agents being covalently attached, or non-covalently attached (biotin-avidin-biotin interaction), as suggested by CALLAN, and to incorporate a drug such as irinotecan into the shell of the microbubble as suggested by CALLAN.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because the utility of microbubbles for delivery of anticancer agents was known prior to the time of the claimed invention, and it would have been within the ordinary level of skill in the art to produce and administer the same to pancreatic cancer patients. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Claims 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over CARPENTER in view of Chen et al.; BAYEVER and Suker et al. as applied to claims 1, 3-9, 14, 16-18, 21, 27 and 28 above, and further in view of Alvarez et al. (“Management of hyperbilirubinaemia in pancreatic cancer patients,” 2018; ELSEVIER; European Journal of Cancer, Vol. 94, pp. 26-36).
Applicants Claims
Applicant claims a method of treating cancer in a patient in need thereof, said method comprising the steps of: (1) administering to affected cells or tissues of said patient an effective amount of a microbubble-chemotherapeutic complex which comprises a microbubble carrying a combination of chemotherapeutic agents, as discussed above. Applicant further claims the patient class encompasses patients with an Eastern Cooperative Oncology Group performance status of greater than 1 (claim 19), and wherein the patient suffers from hepatic or renal dysfunction (claim 20).
Determination of the scope
and content of the prior art (MPEP 2141.01)
CARPENTER teaches a microsphere-antineoplastic agent composite for drug delivery using ultrasonic energy to rupture and release the drug(s), as discussed above and incorporated herein by reference.
Chen et al. teaches microbubbles for delivery of chemotherapeutic drugs to solid tumors, as discussed above and incorporated herein by reference.
BAYEVER teaches treatment of pancreatic cancer by a liposomal formulation of irinotecan, 5-FU and folinic acid, as discussed above and incorporated herein by reference.
Suker et al. teaches that “Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population.”, as discussed above and incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of CARPENTER et al. is that CARPENTER et al. do not expressly teach the patients ECOG performance status or the patients hepatic or renal status.
Alvarez et al. teaches management of hyperbilirubinaemia in pancreatic cancer (title, see whole document), and particularly that: “Development of hyperbilirubinaemia is common in patients with advanced pancreatic adenocarcinoma, both at diagnosis as well throughout disease evolution. For this reason, hyperbilirubinaemia determines chemotherapy treatment selection, and therefore it should be considered one of the most relevant conditions.” [emphasis added](abstract)(instant claim 17). Alvarez et al. teaches that: “In patients with hyperbilirubinaemia, an increase in bilirubin and transaminases occurred more frequently. The study concluded that patients with elevated bilirubin levels have an increased risk of hepatic toxicity, and a dose reduction (20%) is recommended [29].” (p. 31, col. 2, lines 8-13). Alvarez et al. teaches the “Global evaluation of PDAC patients with hyperbilirubinaemia”, including treatment for ECOG PS of up to 2, and including hepatic tumor infiltration (hepatic dysfunction)(p. 33, Figure 2).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a method for the treatment of pancreatic cancer by ultrasound microbubbles carrying a combination of chemotherapeutic agents, and particularly 5-FU, irinotecan and oxaliplatin with administration of folinic acid (leucovorin) which combination was known as FOLFIRINOX, as discussed above, and to treat patients having ECOG status of greater than 1, and hepatic or renal dysfunction, as suggested by Alvarez et al., in order to provide the best possible patient outcome.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because the utility of microbubbles for delivery of anticancer agents was known prior to the time of the claimed invention, and it would have been within the ordinary level of skill in the art to produce and administer the same to pancreatic cancer patients. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Response to Arguments:
Applicant's arguments filed XXX have been fully considered but they are not persuasive.
Applicant argues that: “The teachings of Callan would not have motivated the skilled person to load the claimed combination of highly toxic chemotherapeutic agents onto a single microbubble, let alone to employ the loaded microbubble in a method which does not involve sonodynamic therapy. The teachings of Chen et al., Bayever, and Suker et al. do not remedy the fundamental deficiencies of Callan. None of these references demonstrate the successful implementation of a therapy to treat cancer in which multiple chemotherapeutic agents are loaded onto a single microbubble.” (p. 7, 3rd paragraph).
In response the examiner argues that CARPENTER (newly cited) clearly teaches the treatment of cancer by ultrasound rupturing of microbubbles comprising anticancer drugs, particularly “CARPENTER teaches that: “As illustrated in FIG. 2 and FIG. 3, the gas microsphere liposome composite (1) (MSLC) includes liquid- filled liposomes (7) (LFLs) attached to the lipid (5) or surfactant ( 6). The presence of liquid-filled liposomes (7) stabilizes the surfactant-encapsulated or lipid-encapsulated gas-filled microsphere (3).” ([0059]). And further that: “As illustrated in FIG. 2 and FIG. 3, one or more of the LFLs (7) may include one or more suitable drugs (e.g., therapeutic agents (9) and/or diagnostic agents (9)) in the liquid-filled internal volume. Each of the liquid-filled liposomes (7) may independently include one or more drugs (e.g., therapeutic agents (8) and/or diagnostic agents (9)) in the liquid interior (10) of the liquid-filled liposomes (7). The LFLs (7), when attached to the surfactant-coated or lipid-coated gas-filled microsphere (3) surface, can be burst upon ultrasound stimulation and release the one or more therapeutic drugs (e.g., therapeutic agents (8)) in a diseased organ or tissue in a localized and concentrated fashion. High energy ultrasound is generally capable of causing the gas-filled microsphere (3) to expand and contract rapidly, which eventually leads to gas bubble rupture. The ultrasound energy captured by the gas-filled microsphere (3) will cause the MSLC (1) to fragment and rupture, in turn, releasing the one or more drugs (e.g., therapeutic agents (8)) contained in the interior of the LFLs (7) attached to the surface of the MSLC (1).” ([0064]).
Applicant further argues that: “Applicant also submits that one of ordinary skill in the art at the time of the invention would have lacked a reasonable expectation of success in producing the claimed invention. Based on the teachings of the cited art and in view of the known challenges relating to the implementation of ultrasound-targeted microbubble destruction (UTMD)-mediated delivery of chemotherapeutics, one of ordinary skill in the art would have had no reasonable expectation of success in loading all three highly toxic drugs onto a single bubble in order to provide a therapeutically effective treatment with minimum adverse side-effects for the patient.” (p. 7, 4th paragraph).
In response the examiner cites Applicants Specification disclosing that: “The chemotherapeutic agents herein described may be carried by the microbubble, i.e. attached to or otherwise associated with the microbubble, using various methods including those which are known in the art.” ([0044], as published). And that: “In one embodiment, one or more of the selected chemotherapeutic agents may be attached to the microbubble via strong non-covalent bonding, for example via a biotin-avidin interaction.” ([0045], as published). And further that: “In one embodiment, one or more of the selected chemotherapeutic agents may be attached to the microbubble via one or more covalent bonds, e.g. via a single covalent bond.” ([0048]). And further that: “Alternatively, methods for covalent attachment of a
chemotherapeutic may involve the formation of a "functionalised lipid" which is covalently bound to the chemotherapeutic before preparation of the microbubble-complex.” ([0049]). The examiner notes that the prior art (including numerous CALLAN references) clearly teach producing and “loading all three highly toxic drugs onto a single bubble in order to provide a therapeutically effective treatment with minimum adverse side-effects for the patient”, accordingly Applicants argument is not convincing.
Applicants position that: “Applicant's finding of an improvement for the claimed therapeutic method over conventional FOLFIRINOX treatment is also highly unexpected in light of the teachings of the cited art. Contrary to the Examiner's suggestion, Applicant submits that one of ordinary skill in the art would not have had a reasonable expectation of success in producing the claimed invention based on the knowledge in the art at the time of the invention.” (p. 9, 5th paragraph).
In response the examiner argues that one of ordinary skill would have expected an anticancer drug or drugs delivered directly to the site of action to have an improved efficacy over the same systemically administered. CARPENTER teaches: “The formulation can deliver a higher level of active drug per gas-filled microsphere to a given tissue, relative to known formulations, thereby achieving the intended therapeutic benefit of high concentrations of drug or gene in the region of pathology.” ([0026]).
Applicant argues that: “Applicant's discovery that a low potency 5-fluoropyrimidine (5-FU or its prodrug form, 5-FUR), in combination with two further chemotherapeutic drugs (irinotecan and oxaliplatin or its prodrug form, Pt(DACH)(Ox)(OH)2), can safely be delivered to a target tumor in vivo and achieve the desired therapeutic effect is contrary to expectation based on the teachings of the cited art. Contrary to the Examiner's suggestion, Applicant's proposal to deliver the claimed combination of chemotherapeutic agents (i.e. the FOLFIRINOX treatment) "on a bubble" via ultrasound destruction of the bubble is not obvious in light of the cited art. The cited art does not motivate one of ordinary skill in the art to load the claimed combination of chemotherapeutic agents onto a single microbubble, or to employ the loaded microbubble in the absence of sonodynamic therapy. Moreover, the effects demonstrated in the Examples of the application are "beyond expectation", since one of ordinary skill in the art would not expect the treatment to be successful.” (paragraph bridging pp. 10-11).
In response the examiner argues that Applicants own prior art, particularly WO 2018/220376 A1 clearly teaches methods for covalently and non-covalently attaching, or incorporating the chemotherapeutic agents into the microbubbles. CARPENTER clearly teaches the treatment of cancer by microbubbles ruptured using ultrasound, which is different from sonodynamic therapy in not including a sonosensitizing agent. The cancer treatment using microbubbles without a sonosensitizing agent would have been clearly obvious before the time of the claimed invention (MPEP 2123-I/II – “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments.” and “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use."”).
Applicant argues that: “As evidenced by the results in the Examples of the application, the claimed therapy is associated with a significant improvement in tumor growth delay and survival advantage when tested in mice bearing ectopic KPC pancreatic tumors and subcutaneous HT-29 colon tumors. Importantly, these effects are observed when the chemotherapeutic agents are used at subtherapeutic doses, i.e. at doses which, when used in the standard treatment, would be ineffective. This is expected to significantly reduce the toxicity of the treatment compared to the standard FOLFIRINOX treatment (as described in Suker et al., for example).” (p. 11, 2nd paragraph). And that: “Applicant's invention thus provides an improved FOLFIRINOX treatment, more specifically a FOLFIRINOX treatment that not only improves tumor growth delay (i.e. is of higher therapeutic efficacy) but which achieves this improvement when using doses of each of the highly toxic chemotherapeutics that are significantly lower than those used in conventional FOLFIRINOX treatment. This reduces the overall toxicity and minimizes adverse effects of the treatment. That such an improvement could be achieved in both efficacy and safety is highly unexpected in light of the cited art. Indeed, it is unexpected that three different payloads could be loaded onto a microbubble without adversely impacting the acoustic properties of the bubble and that these could be loaded in sufficient amounts to achieve a therapeutically effective dose of each agent at the target site, even when taking account of known cavitation effects associated with UTMD.” (p. 11, 3rd paragraph). And further that: “When seeking any new medical treatment, it is important that this should not only be effective in treating the condition but also that it must be safe for the patient. Callan notes the significant side-effects associated with conventional FOLFIRINOX treatment and the solution to this which is to limit the treatment to those patients who are otherwise fit and healthy (paragraph [0009]). This limits the number of patients who can benefit from the treatment.” (p. 11, 4th paragraph). And further that: “The ability to reduce the toxicity and thus minimize the adverse effects of conventional FOLFIRINOX treatment in which the highly toxic combination of chemotherapeutic drugs is systemically administered represents a significant advance in the treatment of cancer, such as metastatic pancreatic cancer.” (paragraph bridging pp. 11-12). And further that: “Applicant's invention provides a treatment which is not only highly effective in delaying tumor growth, but which is also associated with reduced side-effects. As described in the application, the claimed therapy can thus be used to treat patients who would not otherwise be eligible for conventional FOLFIRINOX treatment under existing treatment guidelines, i.e. patients who do not have a good ECOG performance status. In contrast to conventional FOLFIRINOX treatment in which an initial "full dose" FOLFIRINOX treatment will often be followed by one or more additional "dose-modified" FOLFIRINOX treatments in which the dose is reduced, thereby compromising the efficacy of the treatment, no such reduction in dose is required when treating a patient in accordance with the claimed treatment, i.e. further courses of treatment need not be "dose-modified". The reduced toxicity of the treatment also means that it has the potential for use as a second-line treatment. This is in contrast to conventional FOLFIRINOX therapy which is not generally recommended as a second-line treatment due to the patient's lower tolerability to a further line of treatment after first-line chemotherapy.” (p. 12, 2nd paragraph).
In response the examiner does not see any unexpected results commensurate with the claims, particularly micro/nano formulations of drug are clearly recognized to have improved efficacy relative to systemic drug in the area of cancer therapy. Additionally, micro/nano formulations of drug typically require lower amounts of drugs, and are delivered directly to the cancer therefore predictably reducing side-effects relative to systemic delivered drugs (MPEP §716.02(c)-II expected beneficial results are evidence of obviousness).
Applicant further argues that: “The problem of drug loading is recognized in Chen et al., which provides an overview of UTMD as a technique for non-invasive, targeted drug delivery. Specifically, Chen et al. states (page 4, final paragraph): […] In respect of the limited drug loading capacity of the microbubble and the options for addressing this problem, Chen et al. further states (page 6, passage bridging right and left-hand columns): […]. Chen et al. thus not only recognizes the problem of drug loading capacity, but also cautions that the acoustic behavior of the microbubble could be altered when increasing drug loading levels.” (pp. 14-15).
In response the examiner argues that the claims are directed to methods of use and not methods of making, the claims do not limit the amount of any drug or drug(s) therefore, Applicants augment is not commensurate with the claims.
Applicant argues that: “In summary, it is again submitted that one of ordinary skill in the art at the time of the invention would have lacked motivation to combined the teachings of the cited art to arrive at the invention as recited in the amended claim set presented herein.” (p. 16, 6th paragraph).
The examiner respectfully disagrees. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a method for the treatment of pancreatic cancer by ultrasound microbubbles carrying a combination of chemotherapeutic agents, and particularly 5-FU, irinotecan and oxaliplatin with administration of folinic acid (leucovorin) which combination was known as FOLFIRINOX, as this drug combination is clearly suggested by the prior art as effective for the treatment of pancreatic cancer, CARPENTER teaching microbubbles for the treatment of cancer, and BAYEVER and Suker et al. suggest this combination of drugs, and the administration of folinic acid with 5-FU is also the combination of drugs being attached to the microbubbles, as suggested by CARPENTER, or alternatively incorporated into the microbubbles shell, as suggested by Chen et al., and particularly given that Suker et al. teaches improved survival of FOLFIRINOX patients vs. gemcitabine (standard of care for patients with locally advanced pancreatic cancer).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “multiple chemotherapeutic agents are loaded onto a single microbubble” – p. 17, lines 1-2) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
Claims 1, 3, 6-14, 16-21 and 26-28 are pending and have been examined on the merits. Claims 17 remains rejected under 35 U.S.C. 112(b); and claims 1, 3, 6-14, 16-21 and 26-28 are rejected under 35 U.S.C. 103.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619