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 .
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 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.
Priority
The instant application, filed 11/04/2022, is a continuation of PCT/US2021/031172, filed 05/06/2021, and claims domestic benefit to US provisional applications 63/020,920, filed 05/06/2020, and 63/020,911, filed 05/06/2020.
Status of Claims/Application
The preliminary amendment of 07/07/2023 is acknowledged. Claims 2, 5-8, 11, 13, 15, and 17-19 are amended and claims 3-4, 20-21, and 23-50 are cancelled.
Claims 1-2, 5-19, and 22 are currently pending and are examined on the merits herein.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Page 22, [0091] recites the following hyperlink that contains non-top-level domain browser-executable code (bolded for clarity):
www.accessdata.fda.gov/drugsatfdadocs/label/2013/2043 691b1.pdf
Appropriate correction is required.
Claim Objections
Claim 18 is objected to because of the following informalities:
Line 2 of the claim recites “RM-131 (or BIM-28131)”. It is suggested that the “or” be removed to clearly identify BIM-28131 as an alternative name for RM-131 and for consistency with the remainder of the claim which identifies synonymous names in parentheticals without the use of “or”.
Additionally, the claim recites at least the following ghrelin variants twice:
EP 1572: once in line 3 and again in line 6; and
GHRP-6: once in lines 2-3 and again in line 8.
It is suggested that the redundant recitations be removed.
Claim 19 is objected to because of the following informalities: the claim recites at least the following duplicate cancer types:
Chondrosarcoma: once on line 5 and again on line 11;
Pancreatic cancer: once on lines 2-3 and again on line 14;
Melanoma: once on line 3 and again on line 21;
Neuroblastoma: once on line 4 and again on line 21; and
Retinoblastoma: once on line 3 and again on line 21.
It is suggested that the redundant recitations be removed.
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 13 and 18-19 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 13 depends on claim 12 and recites the limitation that the meal is a “low-fat” meal. The term “low-fat” is a relative term which renders the claim indefinite. The term “low-fat” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Appropriate correction is required.
Claim 18 recites the limitation “macimorelin (acetate)” in line 7. Acetate indicates an acetate salt of macimorelin which is a narrower embodiment of the preceding limitation. As such, the recitation of acetate in parentheticals renders the claim indefinite as it is unclear if the claim is to macimorelin or an acetate salt of macimorelin.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 18 recites the broad recitation macimorelin, and the claim also recites (acetate) indicating macimorelin acetate which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 19 depends on claim 2 and further limits the type of cancer. The claim recites a list of cancers and uses several conjunctions, such as “and” and “or”, rendering the metes and bounds of the claim indefinite. For instance, the claim recites the conjunction “and” on lines 7 and 10 and “or” on line 21. The use of additional “and” recitations renders the claim indefinite as it is unclear if the claim requires more than one of the recited cancers or if the claim requires one of the recited cancers.
Appropriate correction is required.
Claim 19 recites the following limitations which include indefinite language:
Lines 6-7: “acute myelocytic leukemia (including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia)”. The use of parentheticals in the limitation renders the metes and bounds of the claim indefinite as it is unclear if the narrower embodiments, specifically the types of AML recited in the parentheticals, are limiting features of the claimed invention or exemplary embodiments.
Lines 7-8: “chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia)). The use of “e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Additionally, the recitation of narrower embodiments, specifically the types of chronic leukemias, within parentheticals renders the metes and bounds of the claim indefinite as these are narrower embodiments of the preceding limitations.
Line 9: “lymphomas (e.g., Hodgkin’s disease and non-Hodgkin’s disease)”. The use of “e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Additionally, the recitation of narrower embodiments, specifically the types of chronic leukemias, within parentheticals renders the metes and bounds of the claim indefinite as these are narrower embodiments of the preceding limitations.
Line 10: “such as”. The phrase “such as” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 2, 5, and 7-9 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Hiura, Y., et al (2012) Effects of ghrelin administration during chemotherapy with advanced esophageal cancer patients Cancer 118; 4785-94.
Hiura teaches that cisplatin reduces plasma ghrelin levels through the 5-hydroxytryptamine (5-HT) receptor. This may cause cisplatin-induced gastrointestinal disorder and hinders the continuation of chemotherapy. Hiura reports a prospective, randomized phase 2 trial to evaluate the effects of exogenous ghrelin during cisplatin-based chemotherapy (abstract, background).
In the study presented by Hiura, forty-two patients with esophageal cancer who were receiving cisplatin-based neoadjuvant chemotherapy were assigned to either a ghrelin group or a placebo group. They received either intravenous infusion of synthetic human ghrelin or saline twice daily for 1 week with cisplatin administration (abstract, methods). Enrolled patients received cisplatin-based chemotherapy consisting of either 5-fluorouracil, cisplatin, and doxorubicin (ACF) or 5-fluorouracil, cisplatin, and docetaxel (DCF). Both regimens entailed 2 treatments every 4 weeks (page 4786, right column, Neoadjuvant chemotherapy regimen).
Patients who were assigned to the ghrelin group received ghrelin treatment at a dose of 3 μg/kg body weight diluted in 50 mL saline given over 30 minutes twice daily, before breakfast and before dinner, for 7 consecutive days (page 4787, left column, study protocol).
Adverse events were evaluated each day of chemotherapy and scored by the most severe in the first cycle based on the toxicity grading criteria from the CTCAE by each primary physician (pages 4786-4787, paragraph bridging columns). Dose modifications in the second cycle were based on treatment-related adverse events recorded in the first cycle. If certain hematogenic toxicities were found, doses of cisplatin and doxorubicin/docetaxel were reduced by 20% (page 4787, left column, paragraph 2).
Patients in the ghrelin group had fewer adverse events during chemotherapy related to anorexia and nausea than patients in the control group. Significant deterioration was noted after chemotherapy in the placebo group in quality of life (QoL) scores, appetite, nausea and vomiting, and global health status (abstract, results).
Exogenous ghrelin, as expected, successfully increased oral intake and nutritional status and also maintained QoL during chemotherapy. Hiura teaches that the ultimate objective is to ease the completion of chemotherapy and enhance the overall antitumor effect. In the presented study, the required dose modifications in the second cycle of chemotherapy tended to be fewer in the ghrelin group, 6 patients; 30%, compared to the placebo group, 10 patients; 50%. The provided results suggest that ghrelin can prevent some adverse events directly in addition to its indirect effects through improvement of nutritional status (page 4793, left column, paragraph 3).
Hiura concludes that the presented study demonstrated short-term administration of exogenous ghrelin at the start of cisplatin-based chemotherapy stimulated food intake and minimized adverse events. Hiura believes that ghrelin administration could increase the efficacy of chemotherapy and recommends the use of ghrelin in clinical practice (page 4793, right column, paragraph 3).
As discussed above, Hiura teaches that administration of ghrelin with cisplatin-based chemotherapy allowed for reduced dose modifications in patients. Hiura teaches that 30% of patients receiving ghrelin required dose modification, specifically a 20% reduction in the chemotherapy dose, compared to 50% of the patients in placebo groups. The results presented meet the instant claim limitation of the method increasing dose intensity as the addition of ghrelin allowed for higher doses of chemotherapy compared to control groups. As Hiura teaches that the ghrelin treated patients were able to receive higher doses, dose intensity was increased in these patients. It is noted that, while Hiura does not teach increasing dose frequency and/or duration, instant claim 2 uses the conjunction “and/or”, indicating that increases in only one of dose intensity, frequency, or duration are required.
Thus, the teachings of Hiura anticipate instant claims 2, 5, and 7-9.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over US 2009/0043074 A1 (Mintz, L.) 12 Feb 2009 in view of US 2017/0274049 A1 (Wing, P. and W.L. Yang) 28 Sep 2017.
US’074 teaches the use of ghrelin splice variant, or an analogue thereof, for the preparation of a medicament for one or more of: treatment and/or prevention of loss of body weight and body fat, prophylaxis or treatment of cachexia, stimulation of appetite, stimulation of food intake, stimulation of weight gain, or increasing body fat mass, or increasing body lean mass. The compounds also treat or prevent cachexia and/or lipodystrophy and/or muscle wasting and conditions related thereto. US’074 teaches the use of a ghrelin splice variant-like compound for the preparation of a medicament for the prophylaxis or treatment of cancer cachexia in an individual in need of such treatment (abstract; page 1, [0002]).
US’074 teaches methods for producing the ghrelin splice variant-like compound teaching that it is isolated from lysed cells or from culture media and purified (page 18, [0200]), indicating that it is an isolated ghrelin splice variant-like compound. US’074 teaches that “isolated” is used to describe the ghrelin splice variant like compounds, i.e, polypeptides and nucleotides that have been identified and separated and/or recovered from a component of its natural environment (page 6, [0047]).
US’074 teaches that particularly in relation to cancer cachexia, administration of a secretagogue, such as a ghrelin splice variant-like compound, may be performed in combination with any anti-cancer therapy, including antineoplastic chemotherapy, radiotherapy, and surgical treatment. In particular, it is used in combination with chemotherapy and radiation (page 26, [0294]). US’074 teaches a method of treating cancer comprising administering an effective amount of anti-neoplastic chemotherapy and an effective amount of a secretagogue, such as a ghrelin splice variant-like compound. The treatment with the secretagogue can be started before the chemotherapy treatment initiates and may be continuously administered during chemotherapy (page 26, [0295]). US’074 defines “secretagogue” as a substance stimulating growth hormone release, such as a ghrelin or a ghrelin-like compound. A secretagogue may, for example, be selected from L-692-429, L-692-585, MK677, G-7203, G-7039, G-7502, NN703, or ipamorelin (page 6, [0057]).
US’074 further teaches that the combination treatment may also be co-formulations of the secretagogue, such as ghrelin splice variant-like compound, and the antineoplastic chemotherapy (page 26, [0296]).
US’074 teaches that the treatment is capable of affording the individual treated with improved quality of life (QoL), for example as evidenced by improved appetite and/or body weight and/or nutritional status and/or physical function (page 10, [0118]);
US’074 further teaches that the core of cancer cachexia syndrome relates to the problem of progressive tumor growth and the catabolic side effects of conventional anti-neoplastic therapy. These two phenomena give rise to alterations in the neuro-endocrine system, to the production of a variety of pro-inflammatory cytokines, and to the release of cancer-specific cachectic factors. In turn, these mediators cause a reduction in food intake, abnormality in the metabolism, or a combination of these two (page 7, [0066]). Cancer cachexia is reported to occur in about half of all cancer patients and is associated with more than 20% of cancer deaths. The condition often occurs during advanced cancer, in particular when metastatic tumors are present in the body. Specific cancers are also consistently identified where the frequency of cancer cachexia is particularly high including upper GI cancers, such as pancreas, stomach, esophagus, and liver; lung cancer, in particular small cell lung cancer; head and neck cancer; colorectal cancer; and other solid tumors. Involuntary weight loss has been associated with an approximate 50% drop in survival and decreased tolerance of cancer therapy. Cancer sites associated with the greatest risk for weight loss are those affected by the aerodigestive track and the gastrointestinal system. Furthermore, at the moment of diagnosis, 80% of all patients with cancer of the upper GI tract and 60% of those with lung cancer have already experienced substantial weight loss. On average, the prevalence of cachexia increases from 50% to more than 80% before death and, in more than 20% of the patients, cachexia is the main cause of death (page 7, [0067]).
US’074 teaches a method in which a secretagogue, such as an isolated ghrelin splice variant-like compound, is administered in combination with an anti-cancer therapy such as chemotherapy or radiotherapy to treat cancer cachexia. US’074 also teaches that cachexia is reported to occur in about half of all cancer patients and is associated with more than 20% of cancer deaths.
US’074, however, does not explicitly disclose that the administration increases survival or progression free survival in the subject.
US’049 teaches methods for mitigating radiation injury in a subject following irradiation of the subject above ambient levels comprising administering to the subject ghrelin in an amount effective to mitigate injury due to radiation (page 2, [0020]). The subject, for example, can be undergoing radiation therapy for treatment of a disease, such as cancer (page 2, [0021]).
US’049 tested ghrelin administration in rats that were exposed to whole body irradiation. Rats were exposed to WBI and randomly assigned to sham (non-irradiated), treatment, or vehicle groups. Rats in the treatment group received human ghrelin subcutaneously once a day for 6 days after WBI. In the vehicle group, human ghrelin was replaced with an equivalent volume of normal saline (NS) (page 4, [0041]). US’049 teaches that ghrelin improved survival after whole body irradiation. When WBI rats were treated with human ghrelin once a day for 6 days starting 24 hours after WBI, the survival rate was 63%, which was significantly higher than the vehicle group. When treatment was initiated at 48 hours after WBI, the survival rate remained significantly high at 61%. This survival benefit was evident in the percent body weight change where the majority of the rats in the vehicle group continued to lose weight and succumbed to death whereas those in the treatment group showed consistent increases in body weight and survived (page 5, [0054]; Figures 1A-1D).
US’049 teaches that, in both rodents and humans, cisplatin, a chemotherapy agent, markedly decreases plasma ghrelin concentrations and ghrelin treated stimulated food intake and minimized adverse effects. To evaluate whether ghrelin level in circulation is altered after whole body irradiation, ghrelin was measured in plasma samples from sham and WBI-treated animals. At day 7 post WBI, ghrelin levels were significantly decreased by 27% (page 5, [0055]).
Based on the teachings of US’074, one of ordinary skill in the art would have reasonably expected that treating cancer with ghrelin, or a variant thereof, in combination with chemotherapy would result in increased survival. The teachings of US’094 further support a reasonable expectation of increased survival. As discussed above, US’074 teaches administration of a secretagogue, including ghrelin or a variant thereof, in combination with chemotherapy for the treatment of cachexia in cancer patients. US’074 also teaches that cachexia is associated with more than 20% of cancer deaths and can be caused either in whole or in part by anti-cancer treatments including chemotherapy as well as radiation. As US’074 teaches methods of treating or preventing cancer cachexia caused by chemotherapy, a person of ordinary skill in the art would reasonably expect that cachexia would be reduced and survival would be increased. The reasonable expectation of success is further supported by the exemplary evidence provided by US’094, which demonstrates that, when combined with radiotherapy, ghrelin is able to significantly improve survival compared to controls that received only radiotherapy. While US’094 demonstrates survival with radiotherapy, not specifically chemotherapy, US’094 teaches similarities between radiotherapy and chemotherapy teaching that, like subjects treated with the chemotherapeutic cisplatin, radiation therapy also reduces ghrelin circulation levels demonstrating similar effects of chemotherapy and radiotherapy on ghrelin levels. Additionally, US’074 teaches the combination of ghrelin, or a variant thereof, with chemotherapy or radiation and teaches that both of these treatments result in cachexia that can be treated with ghrelin. As US’094 demonstrates that ghrelin is able to overcome cachexia in patients treated with radiotherapy thereby increasing survival, one of ordinary skill in the art would reasonably expect the same outcome when ghrelin is used in combination with chemotherapy for the treatment of cachexia.
Claims 2, 5-9, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Hiura, Y., et al (2012) Effects of ghrelin administration during chemotherapy with advanced esophageal cancer patients Cancer 118; 4785-94 in view of US 2009/0043074 A1 (Mintz, L.) 12 Feb 2009.
It is noted that claims 2, 5, and 7-9 were rejected above in view of Hiura. The claims are further rejected here to demonstrate that the alternative of a ghrelin variant would have been obvious in view of the prior art.
The teachings of Hiura are as discussed above.
Hiura, however, discloses administration of ghrelin, not a ghrelin variant. Additionally, Hiura discloses treatment of esophageal cancer, not one of the cancers recited in instant claim 19.
The teachings of US’074 are as discussed above.
US’074 further teaches additional cancers that can be treated with the disclosed method including colorectal cancer (page 9, [0101]), colon cancer, pancreatic cancer, melanoma, retinoblastoma, lung cancer, intestine cancer, testicular cancer, stomach cancer, neuroblastoma, lymphoma, osteosarcoma, adenomas, acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, multiple myeloma, Waldenstrom’s Macroglobulinemia, sarcoma, carcinomas, mesothelioma, Ewing’s family of tumors, breast cancer, ovarian cancer, prostate cancer, basal cell carcinoma, renal cell cancer, bile duct cancer, Wilm’s tumor, cervical cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, ependymoma, and esophageal cancer (pages 8-9, [0092]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by Hiura to substitute ghrelin with a ghrelin variant, such as an isolated ghrelin splice variant-like compound, L-692-429, L-692-585, MK677, G-7203, NN703, or ipamorelin, as taught by US’074, and to treat the alternative cancer types taught by US’074. It would have been obvious to substitute the ghrelin for a ghrelin variant and an ordinarily skilled artisan would have had a reasonable expectation of success as US’074 teaches the variants as alternatives to ghrelin for combination with chemotherapy in the treatment of cancer and the treatment or prevention of cancer cachexia suggesting analogous properties. It would have been obvious to treat one of the alternative cancer types taught by US’074 as US’074 suggests the combination of a secretagogue, such as ghrelin or a variant thereof, for the treatment of such cancers. A person of ordinary skill in the art would have had a reasonable expectation of success in treating one of the other cancers as the administration of ghrelin is intended to reduce treatment related cachexia which, based on US’074, could occur with any of the disclosed cancers. Additionally, US’074 teaches esophageal cancer as one of the cancers that can be treated, which is the same cancer tested by Hiura.
Claims 2, 5, and 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Huot, J.R., et al (2019) Chronic treatment with multi-kinase inhibitors causes differential toxicities on skeletal and cardiac muscles Cancers 11(571); 1-20 in view of US 2009/0043074 A1 (Mintz, L.) 12 Feb 2009 and Hiura, Y., et al (2012) Effects of ghrelin administration during chemotherapy with advanced esophageal cancer patients Cancer 118; 4785-94.
It is noted that claims 2, 5, and 7-9 were rejected above over Hiura. The claims are further rejected here to demonstrate that the alternative chemotherapeutic agent, a kinase inhibitor, as recited in claims 8 and 10, would have been obvious in view of the prior art.
Huot teaches that chemotherapeutic drugs, while effectively combating tumors, can also induce debilitating side toxicities, including loss of body weight and muscle mass, along with muscle weakness and fatigue. Altogether, these are hallmarks of cachexia, a comorbidity diagnosed in roughly 80% of subjects with cancer. Cachexia overall significantly increases the likelihood of disease morbidity and mortality and will represent the ultimate cause of death for up to 30% of cancer patients. The occurrence of cachexia is ultimately responsible for the onset of a very debilitating state, such that patients are no longer able to tolerate the anticancer therapies, thus also experience discontinuation of treatment and a hastened demise. Huot teaches that research from their group has highlighted the importance of preserving skeletal muscle among subjects receiving chemotherapy treatments, primarily as an essential modality in improving survival rates in cancer, and several studies have demonstrated a correlation between reduced lean muscle mass, dose-limiting toxicities, and patient’s survival (paragraph bridging pages 1-2).
More than 1.7 million new cases of cancer are expected to be diagnosed by the end of 2019 with chemotherapy administration serving as the preferred treatment option. In an attempt to effectively halt tumor progression and metastasis, waves of alternative therapeutics have surfaced including multi-targeted kinase inhibitors (MKIs), two of which, namely sorafenib and regorafenib, have shown significant survival rate improvement in various cancers including hepatocellular carcinoma, metastatic colorectal cancer, and advanced gastrointestinal stromal tumors (page 2, paragraph 2).
Animals treated with either regorafenib or sorafenib for up to six weeks failed to gain weight compared to vehicle-treated littermates. Overall, the treated animals displayed a reduction in net weight change compared to vehicle littermates over the course of 6 weeks of -85% for regorafenib treated animals and -61% in sorafenib treated animals. Hout teaches that MKI administration was associated with muscle wasting (page 2, 2.1).
Huot, however, does not teach the administration of ghrelin or a ghrelin variant or that the administration of ghrelin or a ghrelin variant with the MKIs, such as regorafenib or sorafenib, allows for increased dose intensity, dose frequency, and/or duration of treatment.
The teachings of US’074 and Hiura are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by Huot, in which cancer is treated with MKIs, including regorafenib, to further include administration of ghrelin or a ghrelin variant as disclosed by US’074. One of ordinary skill in the art would have reasonably expected that the administration of ghrelin would allow for increased dose intensity based on the teachings of Hiura.
An ordinarily skilled artisan would have been motivated to further administer ghrelin or a ghrelin variant in order to prevent or treat cachexia and muscle wasting that has been associated with administration of MKIs, including regorafenib, particularly as both Huot and US’074 teach that cancer cachexia leads to a significant number of deaths. One of ordinary skill in the art would have had a reasonable expectation of success as Huot teaches administration of chemotherapeutics and regorafenib for the treatment of cancer and cachexia related effects and US’074 teaches the administration of ghrelin and variants thereof with anti-cancer therapies, including chemotherapy, for the treatment of therapy related cachexia. Additionally, Huot and US’074 teaches overlapping cancers including colorectal cancers and gastrointestinal tumors.
An ordinarily skilled artisan would have reasonably expected that the administration of both regorafenib and ghrelin or a variant thereof would lead to increased dose intensity compared to administration of the regorafenib alone based on the teachings of Hiura which demonstrate that, when administered ghrelin, subjects required less dose reduction due to toxic events compared to administration of chemotherapy alone. Additionally, Huot teaches that cachexia results in the onset of a debilitating state such that patients are no longer able to tolerate the anticancer therapies and experience discontinuation of treatment and a hastened demise. Teaching which suggest that, by treating cachexia, patients can have increased duration of treatment as discontinuation would no longer be necessary.
Claims 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Hiura, Y., et al (2012) Effects of ghrelin administration during chemotherapy with advanced esophageal cancer patients Cancer 118; 4785-94 in view of Goldstone, A.P., et al (2014) Ghrelin mimics fasting to enhance human hedonic orbitofrontal cortex, and hippocampal responses to food Am. J. Clin. Nutr 99; 1319-1330.
Hiura teaches the method of claim 2 as discussed in detail above.
Hiura, however, discloses administration of the ghrelin before meals. Hiura does not disclose that the ghrelin is administered after the subject has consumed a meal that is low-fat with less than about 30% fat.
Goldstone teaches that ghrelin is a stomach-derived hormone that increases with fasting and energy restriction and may influence eating behaviors through brain hedonic reward-cognitive systems (abstract, background). Goldstone teaches that plasma ghrelin concentrations rise with acute fasting and a chronic negative energy balance, fall after food intake, and are reduced in obesity. Ghrelin also stimulates hunger and food intake through hypothalamic feeding neuropeptides. In rodents, central ghrelin signaling also has roles in reward-based eating, response to nonfood rewards, food anticipatory behavior, foraging, hoarding and olfactory responses, stress-induced overeating, motivation , learning, memory, anxiety, and mood via the stimulation of mesolimbic dopaminergic circuitry, hypothalamus, hippocampus, dorsal raphe serotonergic neurons and other pathways (page 1320, left column, paragraph 2).
Goldstone investigated whether ghrelin administration mimics effects of fasting on the hedonic response and activation of brain-reward systems to food (abstract, objective). In a crossover design, 22 healthy, nonobese adults underwent a functional magnetic resonance imaging food-picture evaluation task after a 16 hour overnight fast or after eating breakfast 95 minutes before scanning. The breakfast contained 730 kcal, 14% protein, 31% fat, and 55% carbohydrates. The subjects received a saline or acyl ghrelin subcutaneous injection before scanning (abstract, design). Compared with the fed-saline population, both ghrelin administration to fed subjects and fasting subjects significantly increased the appeal of high-energy foods associated with orbitofrontal cortex activation. Both fasting and ghrelin administration also increased hippocampus activation to high-energy foods and associated orbitofrontal cortex activation. Both fasting and ghrelin administration also increased hippocampus activation to high-energy and low-energy food pictures (abstract, results). Goldstone teaches that ghrelin administration and fasting have similar acute stimulatory effects on hedonic responses and the activation of corticolimbic reward-cognition systems during food evaluations. (abstract, conclusion).
Figure 1, page 1320, shows the study-visit protocol in which patients were fed breakfast, injected with saline or ghrelin approximately 55 minutes after eating and were given an MRI at 95 minutes (page 1320, Fig. 1; page 1321, right column, Ghrelin injection).
Goldstone teaches that the study shows that, compared with when the same individuals have low endogenous plasma ghrelin concentration after consumption of a meal, both endogenous hyperghrelinemia and exogenous hyperghrelinemia increase food hedonic ratings, OFC, and hippocampus bold signals during food evaluation (page 1329, left column, paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by Hiura to administer the ghrelin approximately 55 minutes after eating a low-fat meal comprising 31% fat based on the teachings of Goldstone. An ordinarily skilled artisan would have been motivated to administer the ghrelin according to Goldstone as Goldstone teaches that ghrelin concentrations in the plasma are lowest after consumption of a meal and demonstrates that ghrelin administration 55 minutes after a 31% fat breakfast significantly increased the appeal of high-energy foods and associated orbitofrontal cortex activation. One of ordinary skill in the art would have had a reasonable expectation of success because Goldstone studied the impact of ghrelin administration on the stimulation of hedonic responses and the appeal of food and Hiura is teaching the administration of ghrelin with chemotherapy as a means to stimulate appetite and food intake thereby increasing weight and minimize gastrointestinal disorders induced by treatment.
A low fat meal comprising 31% fat meets the instant claim 14 limitation of “about 30% fat”. Additionally 31% fat content is close to the claimed range rendering the claimed range obvious per MPEP 2144.05 which states “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.”
Claims 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Hiura, Y., et al (2012) Effects of ghrelin administration during chemotherapy with advanced esophageal cancer patients Cancer 118; 4785-94 in view of Goldstone, A.P., et al (2014) Ghrelin mimics fasting to enhance human hedonic orbitofrontal cortex, and hippocampal responses to food Am. J. Clin. Nutr 99; 1319-1330 as applied to claims 2 and 11 above, and in further view of US 2009/0043074 A1 (Mintz, L.) 12 Feb 2009.
The combination of Hiura and Goldstone teach the method of claim 11 as discussed in detail above.
As discussed above, in the method of Hiura, ghrelin was administered before breakfast and before dinner on consecutive days 1-7 and all participants received intravenous chemotherapy infusions on days 1-7, with cisplatin administration on day 1 (page 4787, left column, study protocol; Figure 1A, page 4788).
As discussed above, Goldstone teaches the administration of ghrelin 55 minutes after a meal. Goldstone further teaches that after the injection at +55 minutes, ghrelin concentrations were significantly higher than when subjects were fed but not administered ghrelin (page 1327, left column, blood hormones and metabolites; Figure 5 and description).
The combination of Hiura and Goldstone, however, do not explicitly disclose that the chemotherapeutic agent is administered after the ghrelin or within about 2 hours of consumption of the meal.
The teachings of US’074 are as discussed above.
US’074 further teaches that ghrelin has a relatively short half-life (page 21, [0232]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by the combination of Hiura and Goldstone to administer the ghrelin before the chemotherapy initiates as suggested by Hiura and taught by US’074. It would have further been obvious to administer the chemotherapy treatment approximately 95 minutes after consumption of the meal based on the teachings of Goldstone.
It would have been obvious to one of ordinary skill in the art to administer the ghrelin before the chemotherapy treatment as Hiura teaches that the ghrelin was administered before breakfast on the days that chemotherapy was administered suggesting that the ghrelin was administered before the chemotherapeutic agents. This is further supported by the teachings of US’074 which teach administration of the secretagogue before chemotherapy treatment initiates. As both Hiura and US’074 teach administration of ghrelin with chemotherapy, one of ordinary skill would have had a reasonable expectation of success.
It would have been obvious to administer the chemotherapy treatment 95 minutes after consumption of the meal as Goldstone demonstrates that when a low-fat meal is consumed and ghrelin is administered 55 minutes after, that at 95 minutes hippocampus activation to high and low-energy food is increased and serum ghrelin concentrations were significantly higher compared to controls. As US’074 teaches that ghrelin has a relatively short half-life and Hiura teaches that cisplatin reduces plasma levels of ghrelin, a person of ordinary skill in the art would be motivated to administer the chemotherapeutic agent while the ghrelin is known to still be present and active in the plasma to avoid serious reduction in ghrelin levels caused by cisplatin administration.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Hiura, Y., et al (2012) Effects of ghrelin administration during chemotherapy with advanced esophageal cancer patients Cancer 118; 4785-94 in view of Goldstone, A.P., et al (2014) Ghrelin mimics fasting to enhance human hedonic orbitofrontal cortex, and hippocampal responses to food Am. J. Clin. Nutr 99; 1319-1330.
The method of Hiura is as discussed above.
Hiura, however, discloses administration of the ghrelin before meals. Hiura does not disclose that the ghrelin is administered with or after a meal.
The teachings of Goldstone are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by Hiura to administer the ghrelin after eating a meal based on the teachings of Goldstone. An ordinarily skilled artisan would have been motivated to administer the ghrelin according to Goldstone as Goldstone teaches that ghrelin concentrations in the plasma are lowest after consumption of a meal and demonstrates that ghrelin administration 55 minutes following a meal significantly increased the appeal of high-energy foods and associated orbitofrontal cortex activation. One of ordinary skill in the art would have had a reasonable expectation of success because Goldstone studied the impact of ghrelin administration on the stimulation of hedonic responses and the appeal of food and Hiura is teaching the administration of ghrelin with chemotherapy as a means to stimulate appetite and food intake thereby increasing weight and minimize gastrointestinal disorders induced by treatment.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693