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 .
Priority
This Application is a 371 of PCT/US21/58278, filed Nov. 5, 2021, and claims priority benefit of U.S. Provisional Application No. 63/110,072 filed Nov. 5, 2020.
Claim Status
Claims 1-3 and 8-23 are currently pending and subject to examination.
Claim Rejections – Withdrawn – Overcome by Amendment
The rejection of claim 16 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn.
The rejection of claims 1-4 and 6-8 under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al. (CN 109172572 A, Published January 11, 2019) is withdrawn.
The rejection of claims 1-4, 6-8 and 15 under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al. (CN 109172572 A, Published January 11, 2019) citing to “Package Insert Granisetron HCl Injection” (Teva, Oct. 2011, p. 1-3) (herein “package insert”) is withdrawn.
The rejection of claims 1-4, 6-8 and 12-15 under 35 U.S.C. 103 as being unpatentable over Chen et al. (CN 109172572 A, Published January 11, 2019), citing to “Package Insert Granisetron HCl Injection” (Teva, Oct. 2011, p. 1-3) (herein “package insert”), as applied to claims 1-4, 6-8 and 15 above, is withdrawn.
The rejection of claims 1-4, 6-8, and 12-16 under 35 U.S.C. 103 as being unpatentable over Chen et al. (CN 109172572 A, Published January 11, 2019) citing to “Package Insert Granisetron HCl Injection” (Teva, Oct. 2011, p. 1-3) (herein “package insert”), as applied to claims 1-4, 6-8 and 15 above, and further in view of Nair et al. (Drug Development Research, Vol. 79, 2018, p. 373–382) is withdrawn.
The rejection of claims 1-4 and 6-15 under 35 U.S.C. 103 as being unpatentable over Chen et al. (CN 109172572 A, Published January 11, 2019), citing to “Package Insert Granisetron HCl Injection” (Teva, Oct. 2011, p. 1-3) (herein “package insert”), as applied to claims 1-4, 6-8 and 23-15 above, and further in view of Kellum et al. (Kidney International, Volume 98, Issue 6, p. 1370-1372, December 2020, published September 9, 2020) is withdrawn.
The rejection of claims 1-4, 6-8, 12-15 and 19 under 35 U.S.C. 103 as being unpatentable over Chen et al. (CN 109172572 A, Published January 11, 2019), citing to “Package Insert Granisetron HCl Injection” (Teva, Oct. 2011, p. 1-3) (herein “package insert”), as applied to claims 1-4, 6-8 and 12-15 above, and further in view of Oh et al. (Scientific Reports, 2019 Feb 26;9(1):2833, p. 1-8) is withdrawn.
The above rejections were overcome by Applicant’s amendments to the claims.
Claim Rejections – 35 USC § 112(b) – Previously Presented
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.”
The rejection of claim 19 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 is maintained.
Response to Arguments
The Applicant argues that the claim amendment obviates the rejection (Remarks, p. 6). These arguments were fully considered but are not persuasive. The claims still recite an improper list of alternatives.
Reiterated Rejection
Claim 19 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claim 19 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Claim 19 is directed towards the method of claim 1, further comprising administering to the patient one or more of: warfarin; lisinopril; heparin; magnesium sulfate; haloperidol; glucagon; metoprolol; furosemide; and hydralazine, or a pharmaceutically-acceptable salt or solvate of any of the preceding.
The compounds: warfarin; lisinopril; heparin; magnesium sulfate; haloperidol; glucagon; metoprolol; furosemide; and hydralazine are not members of the same physical or chemical class and they do not share a common structure or a substantial structural feature. They do not share a common mechanism or therapeutic target. For example, heparin is a blood thinner that binds to antithrombin, metoprolol is a beta-blocker for the treatment of high blood pressure, and glucagon is a hormone that increases blood glucose levels. They do not share a common structure or a substantial structural feature, for example, magnesium sulfate is a simple salt, glucagon is a peptide hormone, heparin is a polysaccharide and metoprolol is propanolamine small molecule. As such, one of ordinary skill in the art would not expect that the alternatives could be substituted for one another and the same results could be achieved.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Furthermore, the alternatives now recite an improper conjunction between the second to last and last members of the group. The conjunction should be “or”.
Claim Rejections - 35 USC § 102 – New Grounds of Rejection
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
“A person shall be entitled to a patent unless -
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.”
Claim(s) 1-3, 12 and 15-17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ross (Vet Clin Small Anim 41 (2011) 1–14).
Claim 1 is directed towards:
A method for treatment of acute kidney injury in a patient in need thereof, comprising administering to the patient a 5-HT3-targeting drug, a 5-HT3A- targeting drug, or a pharmaceutically-acceptable salt or solvate of a 5-HT3-targeting drug or a 5- HT3A-targeting drug, in an amount effective to treat acute kidney injury in the patient, wherein the 5-HT3-targeting drug, the 5-HT3A-targeting drug, or the pharmaceutically-acceptable salt or solvate of a 5-HT3-targeting drug or a 5-HT3A-targeting drug is one or more of ondansetron, dolasetron, palonosetron, alosetron, cilansetron, tropisetron, ramosetron, tubocurarine, clozapine, olanzapine, and metoclopramide or a pharmaceutically-acceptable salt or solvate of any of the preceding.
The specification defines the patient as “an animal, such as a mammal, including… a non-primate (e.g… a dog)” (Specification, p. 6, paragraph 0040). The specification defines “treating” or “treatment” as “a beneficial or desired result, such as improving one of more, or symptoms of a disease. The terms ‘treating’ or ‘treatment’ also include, but are not limited to, alleviation or amelioration of one or more symptoms of acute kidney injury” (id.).
Ross discusses the treatment of acute kidney injury (AKI) in dogs and cats. Ross teaches that vomiting is one of the most common symptoms of uremia in animals with AKI and is treated by administration of the 5HT3-targeting drugs metoclopramide, dolasetron, and ondansetron:
Treatment of other uremic complications
Vomiting Vomiting is one of the most common signs of uremia in animals with AKI. The cause of vomiting is multifactorial; it is centrally mediated by uremic toxins that act on the chemoreceptor trigger zone and locally mediated by uremic gastritis… Metoclopramide, a dopamine antagonist, may be given as intermittent therapy at a dose of 0.2 to 0.5 mg/kg every 8 hours [q8h] IV or as a CRI at 1-2 mg/kg/d IV. Other centrally acting drugs include dolasetron (Anzemet; 0.6 mg/kg q24h PO or SQ or diluted in compatible IV fluid and administered over 15 minutes IV) and ondansetron (Zofran; 0.1–0.2 mg/kg q8h SQ or 0.5 mg/kg IV loading dose, then 0.5 mg/kg/h CRI).
Ross, p. 10.
Therefore, claim 1 is anticipated.
Claim 2 is directed towards the method of claim 1 for treatment of a critically ill patient, comprising administering to the patient a 5-HT3-targeting drug, a 5-HT3A-targeting drug, or a pharmaceutically-acceptable salt or solvate of a 5-HT3-targeting drug or a 5-HT3A-targeting drug, in an amount effective to reduce risk of acute kidney injury in the patient.
The specification states that the therapeutically effective amount of metoclopramide is 1 mg/kg to at least about 2 mg/kg over a period of not less than 15 minutes (Specification, p. 12, paragraph 0059). Ross teaches that the therapeutically effective amount of metoclopramide is 1-2 mg/kg/day given as a continuous rate infusion (CRI) (Ross, p. 10, shown above). The specification teaches that the therapeutically effective amount of ondansetron is 6 mg per day to 96 mg per day (Specification, p. 12, paragraph 0060). Ross teaches that the therapeutically effective amount of ondansetron is 0.5 mg/kg IV loading dose, then 0.5 mg/kg/h CRI (Ross, p. 10, shown above). For a typical 4 kg cat, this would be a daily dose of 50 mg per day (2 mg loading dose followed by 2 mg/ h CRI), falling within the claimed range.
Therefore, claim 2 is anticipated.
Claim 3 is directed towards the method of claim 2, wherein the critically ill patient is: an intensive care unit patient, a critical care unit patient, a patient requiring intensive care or critical care, a sepsis patient, a patient recovering from major surgery (a surgery in which a body cavity is entered), a patient exposed to a nephrotoxin, a patient having a microbial infection that increases risk of acute kidney injury, a kidney transplant recipient, a burn patient, or a critically-injured patient.
Uremic cats and dogs with AKI are critically ill and have a poor prognosis. Ross teaches that the mortality rate for dogs with AKI is 53-60% and in cats, 50% (Ross, p. 11). Ross teaches that the cause of AKI includes sepsis, nephrotoxins, and microbial infections:
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Ross, p. 2.
Therefore, claim 3 is anticipated.
Claim 12 is directed towards the method of claim 1, wherein the 5-HT3-targeting drug, the 5-HT3A-targeting drug, or the pharmaceutically-acceptable salt or solvate of a 5-HT3- targeting drug or a 5-HT3A-targeting drug reduces mortality or increases survival in a population of patients having acute kidney injury.
While Ross does not teach that the HT3A-targeting drug reduces mortality or increases survival in a population of patients having acute kidney injury, this is an inherent property of administering a therapeutically effective amount of the drug. As shown in the rejection of claim 2, Ross teaches to administer a therapeutically effective amount of the drug.
Therefore, claim 12 is anticipated.
Claim 15 is directed towards the method of claim 1, wherein the 5-HT3-targeting drug, the 5-HT3A-targeting drug, or the pharmaceutically-acceptable salt or solvate of a 5-HT3- targeting drug or a 5-HT3A-targeting drug is administered by intravenous injection or infusion.
As shown in the rejection of claim 1, Ross teaches that the 5-HT3-targeting drug can be administered by intravenous injection or infusion: e.g. ondansetron is administered as “0.5 mg/kg IV loading dose, then 0.5 mg/kg/h CRI” (Ross, p. 10).
Therefore, claim 15 is anticipated.
Claim 16 is directed towards the method of claim 1, wherein a total of from 0.5 mg to 200 mg of the 5-HT3-targeting drug, the 5-HT3A-targeting drug, or the pharmaceutically- acceptable salt or solvate of a 5-HT3-targeting drug or a 5-HT3A-targeting drug is administered daily to the patient. Claim 17 is directed towards the method of claim 16, wherein a total of from 6 mg to 96 mg of ondansetron, or a pharmaceutically-acceptable salt or solvate thereof is administered daily to the patient.
Ross teaches that the therapeutically effective amount of ondansetron is 0.5 mg/kg IV loading dose, then 0.5 mg/kg/h CRI (Ross, p. 10, shown above). For a typical 4 kg cat, this would be a daily dose of 50 mg per day (2 mg loading dose followed by 2 mg/ h CRI), falling within the claimed ranges.
Therefore, claims 16-17 are anticipated.
Claim Rejections – 35 USC § 103 – Previously Presented
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.
The rejection of claims 1-3, 8 and 12-18 under 35 U.S.C. 103 as being unpatentable over Chen et al. (CN 109172572 A, Published January 11, 2019) in view of Aapro (The Oncologist, Volume 9, Issue 6, November 2004, Pages 673–686) is maintained.
The Applicant argues that Aapro is directed towards a very narrow therapeutic effect and that the compounds are different in potency, therapeutic activity and specificity (Remarks, p. 6-7). These arguments were fully considered but are not persuasive. Aapro shows that these compounds are in the same class and have the same activity at the 5HT3 receptor (both have a pKi of about 8 at this receptor). Chen indicates that the therapeutic activity of granistetron is due to its 5HT3 targeting effects. As such, one of ordinary skill in the art would reasonably expect that odansetron and granistetron would have similar effects in the treatment of acute kidney injury. The examiner notes that the applicant claims 5HT3 targeting drugs which have more disparate activities than granistetron vs. odansetron. Clozapine and olanzapine are antipsychotics which have entirely different indications than granisetron, odansetron and other similar anti-emetics.
Reiterated Rejection
Claims 1-3, 8, and 12-18 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (CN 109172572 A, Published January 11, 2019) in view of Aapro (The Oncologist, Volume 9, Issue 6, November 2004, Pages 673–686).
Claim 1 is directed towards:
A method for treatment of acute kidney injury in a patient in need thereof, comprising administering to the patient a 5-HT3-targeting drug, a 5-HT3A- targeting drug, or a pharmaceutically-acceptable salt or solvate of a 5-HT3-targeting drug or a 5- HT3A-targeting drug, in an amount effective to treat acute kidney injury in the patient, wherein the 5-HT3-targeting drug, the 5-HT3A-targeting drug, or the pharmaceutically-acceptable salt or solvate of a 5-HT3-targeting drug or a 5-HT3A-targeting drug is one or more of ondansetron, dolasetron, palonosetron, alosetron, cilansetron, tropisetron, ramosetron, tubocurarine, clozapine, olanzapine, and metoclopramide or a pharmaceutically-acceptable salt or solvate of any of the preceding.
Chen teaches a method of treating sepsis kidney injury (a type of acute kidney injury) comprising administering to the patient an effective amount of granisetron, a 5-HT3 receptor antagonist:
The invention claims granisetron in preparing medicine for preventing and treating sepsis organ damage in the application, wherein the sepsis with organ damage is sepsis and renal injury. the application of said medicine is injection, concentration of granisetron in the injection is 1 mg/ml. The Granisetron of the invention can obviously improve the sepsis mouse kidney on the animal level, lung tissue damage and can obviously inhibit the expression of inflammatory factors, inflammatory reaction with a certain relieving effect, and it can be used for preparing medicine for preventing and treating sepsis lung injury and sepsis kidney injury.
Chen, Translation, Abstract;
Granisetron injection is colourless transparent liquid, which is a highly selective 5-HT3 receptor antagonist.
Chen, Translation, Specification, p. 1.
Chen shows that granisetron reduced kidney injury in a mouse model of sepsis induced kidney injury:
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Chen, Fig. 1;
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Chen, Fig. 2 (Cr. is serum creatinine).
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Chen, Fig. 3 (mRNA is renal tissue inflammatory factor TNF).
While Chen does not teach that the 5HT3 drug is ondansetron one of ordinary skill in the art would have a reasonable expectation of success to use ondansetron or granisetron because they are members of the same art recognized class and have been demonstrated to be therapeutic equivalents.
For example, Aapro teaches that granisetron and ondansetron have similar activities at the 5-HT3 receptor and that granisetron 2 mg orally once daily has similar effects to ondansetron 32 mg i.v.:
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Aapro, Table 1, p. 674
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Aapro, Table 3, p. 675.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 2 is directed towards the method of claim 1 for the treatment of a critically ill patient. Claim 3 is directed towards the method of claim 2, wherein the critically ill patient is an intensive care unit patient, a critical care unit patient, a patient requiring intensive care or critical care, a sepsis patient, a patient recovering from major surgery (a surgery in which a body cavity is entered), a patient exposed to a nephrotoxin, a patient having a microbial infection that increases risk of acute kidney injury, a kidney transplant recipient, a burn patient, or a critically-injured patient. Claim 8 is directed towards the method of claim 1, wherein the patient is in an intensive care unit.
One of ordinary skill in the art would have a reasonable expectation of success to treat a critically ill patient in the ICU, particularly a sepsis patient, because 5HT3 targeting drugs are known for the treatment of kidney injury in these patients.
For example, Chen teaches that the patient is a sepsis patient and that these patients are critically ill with a systemic inflammatory reaction which can cause shock, multiple organ dysfunction and high mortality:
Sepsis is that the systemic inflammatory reaction of bacteria, virus or fungal infection, which can cause shock, multiple organ dysfunction syndrome (MODS) and even death. sepsis high incidence, worldwide each year more than 1800 million severe sepsis cases, but the digital further rises with speed of 1.5% to 8.0% per year. In recent years, although infection treatment (antibiotic), intensive care and organ function support technology has obtained remarkable progress, but the hospital mortality rate reaches up to 15% to 50%. sepsis, large amount of inflammatory mediators and inflammatory medium releasing into the blood, resulting in multiple organ function impairment, lymphocyte apoptosis, immune and inflammatory reaction of organism and inflammatory reaction imbalance is considered to be a major mechanism of sepsis. effective medicine at present, clinical treatment of sepsis has not been successfully developed pertinence, is a severe challenge severe medical.
Chen, Translation, Specification, p. 1.
Therefore, claims 2-3 and 8 were prima facie obvious at the time of filing.
Claim 12 is directed towards the method of claim 1, wherein the 5-HT3-targeting drug, the 5-HT3A-targeting drug, or the pharmaceutically-acceptable salt or solvate of a 5-HT3-targeting drug or a 5-HT3A-targeting drug reduces mortality or increases survival in a population of patients having acute kidney injury.
By way of background, Chen teaches that the goal of the invention is to reduce mortality in patients with sepsis as “although infection treatment (antibiotic), intensive care and organ function support technology has obtained remarkable progress… the hospital mortality rate reaches up to 15% to 50%.” (Chen, Translation, Specification, p. 1). Chen teaches sepsis and the associated mortality is caused by a “large amount of inflammatory mediators and inflammatory medium releasing into the blood, resulting in multiple organ function impairment, lymphocyte apoptosis, immune and inflammatory reaction of organism and inflammatory reaction imbalance.” (id.). Therefore, by improving inflammation and reducing organ damage associated with sepsis, mortality would be expected to be reduced.
While Chen does not explicitly show that 5-HT3-targeting drugs reduce mortality or increases survival in patients with acute kidney injury, one of ordinary skill in the art would have a reasonable expectation of success to reduce mortality or increase survival in patients with acute kidney injury because Chen teaches that “granisetron can obviously inhibit the expression of inflammatory factors, inflammatory reaction has certain relieving effect, which can obviously improve the sepsis mouse kidney and lung tissue damage” (Chen, Translation, Specification, p. 2).
Therefore, claim 12 was prima facie obvious at the time of filing.
Claim 13 is directed towards the method of claim 1, wherein the 5-HT3-targeting drug, the 5-HT3A-targeting drug, or the pharmaceutically-acceptable salt or solvate of a 5-HT3-targeting drug or a 5-HT3A-targeting drug is administered once acute kidney injury is detected in the patient, when serum creatinine of the patient increases by 0.3 mg/dl (26.5 pmol/1) or more in 48 hours, when serum creatinine of the patient rises to at least 1.5-fold from baseline within 7 days; when urine output is less than 0.5ml/kg/hr for more than 6 hours (e.g., KDIGO criteria), or when any other approved diagnostic for AKI is positive.
While Chen does not specifically teach commencing treatment when an approved diagnostic for AKI is positive, one of ordinary skill in the art would have a reasonable expectation of success to administer the 5-HT3 targeting drug once acute kidney injury is detected in the patient because Chen teaches the use of granisetron in the treatment of sepsis in the setting of organ damage (Chen, Translation, Specification, p. 2). Chen teaches that “the Granisetron new application specifically, granisetron in pharmacy in preparing medicine for preventing and treating sepsis organ damage in the application, wherein the sepsis with organ damage is sepsis and renal injury.” (id.).
Therefore, claim 13 was prima facie obvious at the time of filing.
Claim 14 is directed towards the method of claim 1, wherein the patient has elevated serum creatinine levels, and the 5-HT3-targeting drug is administered to the patient until serum creatinine levels are normalized in the patient.
While Chen does not specifically teach to administer the 5-HT3 targeting drug until serum creatinine levels are normalized in the patient, one of ordinary skill in the art would have a reasonable expectation of success to administer the 5-HT3 targeting drug until serum creatinine levels are normalized in the patient because Chen teaches that sepsis kidney injury increases serum creatinine levels and that they are lowered by the administration of granisetron:
FIG. 2 CLP + GA group serum creatinine content in obviously reduced with the CLP group (p < 0.05), data description granisetron can reduce sepsis model in mouse kidney injury.
Chen, Translation, Specification, p. 3;
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Chen, Fig. 2 (Cr. is serum creatinine).
Therefore, claim 14 was prima facie obvious at the time of filing.
Claim 15 is directed towards the method of claim 1, wherein the 5-HT3-targeting drug, the 5-HT3A-targeting drug, or the pharmaceutically-acceptable salt or solvate of a 5-HT3-targeting drug or a 5-HT3A-targeting drug is administered by intravenous injection or infusion.
Chen teaches the treatment of sepsis renal injury with granisetron (Chen, Translation, Abstract), such as that used for treating cancer chemotherapy-induced emesis and irritable bowel syndrome (Chen, Translation, Specification, p. 3).
While Chen does not teach intravenous administration of e.g. ondansetron, one of ordinary skill in the art would have a reasonable expectation of success to substitute intravenous ondansetron for granisetron because these regimens are known to be therapeutically equivalent.
For example, Aapro teaches that granisetron and ondansetron have similar activities at the 5-HT3 receptor and that granisetron 2 mg orally once daily has similar effects to ondansetron 32 mg i.v.:
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Aapro, Table 1, p. 674
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Aapro, Table 3, p. 675.
Therefore, claim 15 was prima facie obvious at the time of filing.
Claim 16 is directed towards the method of claim 1,wherein a total of from 0.5 mg to 200 mg of the 5-HT3-targeting drug, is administered daily to the patient, such as in one or more doses or as a continuous or intermittent infusion.
Chen teaches the treatment of sepsis renal injury with granisetron (Chen, Translation, Abstract), such as that used for treating cancer chemotherapy-induced emesis and irritable bowel syndrome (Chen, Translation, Specification, p. 3). Chen teaches that they administered granisetron at a dose of 1 mg/kg in a mouse model of sepsis kidney injury (Chen, Translation, Specification, p. 2).
While Chen does not specifically teach the dose for an adult human patient, one of ordinary skill in the art would have a reasonable expectation of success to administer between 0.5 to 200 mg of the 5-HT3 targeting drug, such as in one or more doses or as a continuous or intermittent infusion because this dose is recognized as a result-effective therapeutic dose for granisetron.
For example, Aapro teaches that i.v. granisetron, 10-40 µg/kg, is effective in preventing acute nausea and vomiting in adult patients (Aapro, col. 2, p. 674). 10-40 µg/kg translates to 0.7 to 2.8 mg for a typical 70 kg adult. Thus, claim 16 was prima facie obvious at the time of filing.
Claim 17 is directed towards the method of claim 16, wherein a total of from 6 mg to 96 mg of ondansetron, or a pharmaceutically-acceptable salt or solvate thereof is administered daily to the patient. Claim 18 is directed towards the method of claim 17, wherein from 4 mg to 32 mg of ondansetron, or a pharmaceutically-acceptable salt or solvate thereof is administered every 8 hours to the patient.
As shown above, Chen teaches that the 5-HT3 antagonist is granisetron.
While Chen does not teach that granisetron can be substituted for ondansetron at a dose of 6 mg to 96 mg daily or 4 mg to 32 mg administered every 8 hours, one of ordinary skill in the art would have a reasonable expectation of success to administer ondansetron because ondansetron and granisetron are members of the same art recognized class and have been demonstrated to be therapeutic equivalents and doses of ondansetron 6 mg to 96 mg daily or 4 mg to 32 mg administered every 8 hours are recognized as result-effective therapeutic doses.
For example, Aapro teaches that granisetron and ondansetron have similar activities at the 5-HT3 receptor and that granisetron 2 mg orally once daily has similar effects to ondansetron 32 mg i.v.:
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Aapro, Table 1, p. 674
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Aapro, Table 3, p. 675.
Citing to the package insert for ondansetron, Aapro teaches that “ondansetron is recommended to be dosed as a single high dose or 2-3 times daily for full efficacy.” (Aapro, col. 2, p. 676). For example, Aapro teaches that ondansetron can be administered at a dose of 8 mg three time daily (every 8 hours):
In a double-blind, randomized trial involving 34 patients, oral granisetron (2 mg, 1 hour before the first daily fraction of radiation) and oral ondansetron (8 mg, 1 hour before each daily fraction) were shown to be more effective at preventing nausea and vomiting in patients receiving hyperfractionated total body irradiation (compared with an historical control group of 90 patients who received the same radiotherapy regimen but no 5-HT3-receptor antagonist)… Over 60% of granisetron patients were without emesis versus 6.7% of patients in the control group; p < 0.01. Ondansetron was similarly superior to the control, but it was dosed three times daily…”
Aapro, col. 1, p. 677.
Therefore, claims 17-18 were prima facie obvious at the time of filing.
Claim Rejections – 35 USC § 103 – New Grounds of Rejection
Claims 1-3, 8-18 and 20-23 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (CN 109172572 A, Published January 11, 2019) in view of Aapro (The Oncologist, Volume 9, Issue 6, November 2004, Pages 673–686), as applied to claims 1-3, 8 and 12-18 above, and further in view of Ronco et al. (Lancet Respiratory Medicine, Vol. 8, July 2020, p. 738-742).
The rejection of claims 1-3, 8 and 12-18 above is incorporated herein by reference.
Claim 9-11 are directed towards the method of claim 1, wherein the patient has a viral infection, coronavirus infection, or SARS-CoV-2 coronavirus (COVID-19) infection, respectively. Claim 20 is directed towards A method for treatment of acute kidney injury in a patient having a viral infection, comprising administering to the patient a 5-HT3-targeting drug, a 5-HT3A-targeting drug, or a pharmaceutically-acceptable salt or solvate of a 5-HT3-targeting drug or a 5-HT3A- targeting drug, in an amount effective to treat acute kidney injury in the patient. Claim 21 limits the 5-HT3A-targeting drug to ondansetron, dolasetron, palonosetron, alosetron, cilansetron, tropisetron, ramosetron, tubocurarine, clozapine, olanzapine, and metoclopramide or a pharmaceutically-acceptable salt or solvate of any of the preceding. Claims 22 and 23 limit the viral infection to coronavirus infection and COVID-19, respectively.
As shown above, Chen teaches the treatment of sepsis kidney injury using 5HT3 targeting drugs. Chen teaches that these types of drugs treat sepsis kidney injury by inhibiting the expression of inflammatory factors and relieving the inflammatory reaction (Chen, Translation, Abstract). As shown above, Aapro teaches that ondansetron and ganistetron are similar 5HT3 targeting drugs.
While Chen does not teach that the kidney injury is experienced by a patient with a viral infection, one of ordinary skill in the art would have a reasonable expectation of success to apply granisetron to a patient with viral or COVID-19 associated kidney injury because it is commonly known in the art that COVID-19 patients can experience acute kidney injury (AKI) similar to traditional bacterial sepsis wherein inflammatory factors lead to kidney injury.
For example, Ronco teaches that COVID-19 leads to cytokine storm which causes acute kidney injury in COVID-19 patients:
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Ronco, p. 739.
Ronco teaches that treatment should target these inflammatory cytokines which contribute to kidney injury, similar to Chen:
In the absence of specific treatment options for COVID-19, care is largely supportive; we recommend the implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) supportive care guideline in critically ill patients at risk of AKI, the use of continuous renal replacement therapy (RRT) with specific adjustments for patients with COVID-19, and the possible use of cytokine removal strategies, ideally in the context of a clinical trial, in patients with early signs of hyperinflammation and cytokine release syndrome.
Ronco, Key messages, p. 738.
Therefore, claims 9-11 and 20-23 were prima facie obvious at the time of filing.
Claims 1-3, 8 and 12-19 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (CN 109172572 A, Published January 11, 2019), in view of Aapro (The Oncologist, Volume 9, Issue 6, November 2004, Pages 673–686), as applied to claims 1-3, 8 and 12-18 above, and further in view of Oh et al. (Scientific Reports, 2019 Feb 26;9(1):2833, p. 1-8).
The rejection of claims 1-3, 8 and 12-18 as obvious over Chen in view of Aapro is incorporated herein by reference.
Claim 19 is directed towards the method of claim 1, further comprising administering to the patient one or more of warfarin; lisinopril; heparin; magnesium sulfate; haloperidol; glucagon; metoprolol; furosemide; and hydralazine, or a pharmaceutically-acceptable salt or solvate of any of the preceding.
While Chen does not teach further administering an additional therapeutic agent, one of ordinary skill in the art would have a reasonable expectation of success to administer an additional therapeutic agent such as magnesium sulfate because it is commonly known in the art that magnesium sulfate infusion can be used as a co-adjuvant drug to reduce the risk of acute kidney injury in at risk patients.
For example, Oh teaches that magnesium sulfate infusion is associated with a reduced risk of acute kidney injury following abdominal surgery:
Magnesium sulfate can be used as a co-adjuvant drug during the perioperative period and has multiple benefits. Recent evidence suggested that perioperative magnesium sulfate infusion may lower the risk of postoperative acute kidney injury (AKI). We investigated the association between intraoperative magnesium sulfate infusion and incidence of AKI after major laparoscopic abdominal surgery. We retrospectively analyzed the medical records of adult patients 20 years or older who underwent elective major laparoscopic abdominal surgery (>2 hours) between 2010 and 2016. We investigated the association between intraoperative magnesium sulfate infusion and the incidence of postoperative AKI until postoperative day (POD) 3 using a multivariable logistic regression analysis. We included 3,828 patients in this analysis; 357 patients (9.3%) received an intraoperative magnesium sulfate infusion and 186 patients (4.9%) developed postoperative AKI by POD 3. A multivariable logistic regression analysis showed that magnesium infusion was associated with a significant decrease (63%) in postoperative AKI (odds ratio, 0.37; 95% confidence interval, 0.14–0.94; P = 0.037). Our study suggested that intraoperative magnesium sulfate infusion is associated with a reduced risk of postoperative AKI until POD 3 for patients who underwent laparoscopic major abdominal surgery. Well-designed, prospective studies should be conducted to further substantiate these findings.
Oh, Abstract (emphasis added).
It is prima facie obvious to combine two therapeutics known for the same purpose and therefore it would be obvious to combine 5HT3-targeting drugs and magnesium sulfate, both known for the treatment/ prevention of acute kidney injury:
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art."… In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
MPEP 2144.06.
Therefore, claim 19 was prima facie obvious at the time of filing.
Claim(s) 1-3 and 12-19 is/are rejected under 35 U.S.C. 103 unpatentable over Ross (Vet Clin Small Anim 41 (2011) 1–14), as applied to claims 1-3, 12 and 15-17 above.
The rejection of claims 1-3, 12 and 15-17 above is incorporated herein by reference.
Claim 13 is directed towards the method of claim 1, wherein the 5-HT3-targeting drug, the 5-HT3A-targeting drug, or the pharmaceutically-acceptable salt or solvate of a 5-HT3- targeting drug or a 5-HT3A-targeting drug is administered once acute kidney injury is detected in the patient, when serum creatinine of the patient increases by 0.3 mg/dl (26.5 tmol/l) or more in 48 hours, when serum creatinine of the patient rises to at least 1.5-fold from baseline within 7 days; when urine output is less than 0.5ml/kg/hr for more than 6 hours (e.g., KDIGO criteria), or when any other approved diagnostic for AKI is positive.
Ross teaches the following diagnostic criteria for AKI, falling with the claimed criteria:
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Ross, p. 4.
While Ross does not explicitly teach administering the 5-HT3A-targeting drug when the patient is diagnosed with AKI, one of ordinary skill in the art would have a reasonable expectation of success to administer the drug once AKI is detected in the patient because veterinary patients with AKI present with AKI. Ross teaches that the RIFLE classification is “is difficult to apply to veterinary patients, because pre-AKI information about serum creatinine concentration and urine output are rarely available.” (Ross, p. 4). Ross teaches further laboratory and imaging assessments for AKI in veterinary patients (Ross, p. 4-5).
Therefore, claim 13 was prima facie obvious at the time of filing.
Claim 14 is directed towards the method of claim 1, wherein the patient has elevated serum creatinine levels, and the 5-HT3-targeting drug, 5-HT3A-targeting drug, or the pharmaceutically-acceptable salt or solvate of a 5-HT3-targeting drug or a 5-HT3A-targeting drug is administered to the patient until serum creatinine levels are normalized in the patient.
Ross teaches that animals should be monitored for elevated creatinine levels (e.g. Ross, p. 7). While Ross does not teach that the 5-HT3 targeting drug is administered until serum creatinine levels are normalized in the patient, one of ordinary skill in the art would have a reasonable expectation of success to administer the drug until serum creatinine levels are normalized in the patient because Ross teaches to administer supportive and specific treatment until renal function returns to normal (Ross, p. 11).
Therefore, claim 14 was prima facie obvious at the time of filing.
Claim 18 is directed towards the method of claim 17, wherein from 4 mg to 32 mg of ondansetron, or a pharmaceutically-acceptable salt or solvate thereof is administered every 8 hours to the patient.
As shown in the rejection of claim 1, Ross teaches that a therapeutically effective amount of ondansetron includes 0.1-0.2 mg/kg q8h SQ (Ross, Specification, p. 10). For a typical 40 kg German Shepherd, a common veterinary patient, this translates to 4-8 mg every 8 hours. This range falls within the claimed range and thus there is a prima facie case of obviousness (MPEP § 2144.05).
Therefore, claim 18 was prima facie obvious at the time of filing.
Claim 19 is directed towards the method of claim 1, further comprising administering to the patient one or more of warfarin; lisinopril; heparin; magnesium sulfate; haloperidol; glucagon; metoprolol; furosemide; and hydralazine, or a pharmaceutically-acceptable salt or solvate of any of the preceding.
While Ross does not explicitly teach the combination of a 5HT3-targeting drug and one or more of the above, one of ordinary skill in the art would have a reasonable expectation of success to administer e.g. furosemide to a patient receiving a 5HT3-targeting drug for the symptoms of AKI because it is commonly known in the art to administer furosemide to patients with AKI.
For example, Ross teaches that the third stage of AKI is characterized by azotemia, uremia, and/or oliguria (Ross, p. 1) and that nausea is a common symptom of uremia and is treated by 5HT3 targeting drugs such as ondansetron (Ross, p. 10). Ross further teaches that animals with oliguria or anuria should be treated with furosemide after hydration so that IV fluid therapy to correct acid-base and electrolyte imbalances can continue. (Ross, p. 8).
Therefore, claim 19 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
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/HEATHER DAHLIN/Examiner, Art Unit 1629