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 .
Claim Status
Claims 1-3, 8-11, and 13-24 are currently pending and subject to examination.
Claim Rejections – Withdrawn – Overcome by Amendment
The rejection of claim(s) 1-3, 12 and 15-17 under 35 U.S.C. 102(a)(1) as being anticipated by Ross (Vet Clin Small Anim 41 (2011) 1–14) is withdrawn.
The rejection of claim(s) 1-3 and 12-19 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103 unpatentable over Ross (Vet Clin Small Anim 41 (2011) 1–14), as applied to claims 1-3, 12 and 15-17 above, is withdrawn.
The rejection of claims 1-3, 8 and 12-19 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 (Scientific Reports, 2019 Feb 26;9(1):2833, p. 1-8) is withdrawn.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 because the claim now only recites blood thinners (Remarks, p. 6). These arguments were fully considered but are not persuasive. The claims still recite an improper list of alternatives because the claim is directed towards warfarin, heparin and metoprolol. While warfarin and heparin are blood thinners, metoprolol is a beta-adrenergic antagonist, an antihypertensive.
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; heparin; metoprolol;, or a pharmaceutically-acceptable salt or solvate of any of the preceding.
The compounds: warfarin; heparin; and metoprolol 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, and metoprolol is a beta-blocker for the treatment of high blood pressure. They do not share a common structure or a substantial structural feature, for example, 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.
Claim Rejections – 35 USC § 102 – New Grounds of Rejection Necessitated by Amendment
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, 8, 13 and 15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Heymer et al. (Indian J Crit Care Med. 2018 Dec;22(12):883–885) as evidenced by “Drugs@FDA, search results for metoclopramide.”
Claim 1 is directed towards a method for reducing mortality or increasing survival in a human patients having an acute kidney injury, 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 mortality or increase survival of 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.
Heymer teaches a method of reducing mortality or increasing survival in a human patient having an acute kidney injury, comprising administering to the patient metoclopramide in an amount effective to reduce mortality or increase survival of the patient:
Repeated vomiting may lead to profound loss of fluid and electrolytes. We describe a case with life-threatening acid-base disturbances due to vomiting. A 38-year-old man presented to an emergency department with weakness and decreased urine output after having vomited up to 20 times per day over a period of 7 days. Arterial blood gas analysis revealed a metabolic alkalosis with partial respiratory compensation. Initial management consisted of oxygen therapy and intravenous fluid therapy with normal saline and potassium chloride. To prevent further gastric losses of HCl, proton-pump inhibitors and metoclopramide were administered. The vomiting was caused most likely by a temporary duodenal stenosis due to portal hypertension of unknown etiology. In our opinion, this case demonstrates the successful management of a life-threatening condition by simple measures. Despite extensive diagnostic procedures, the effective treatment of the underlying condition consisted of watchful waiting.
Heymer, Abstract;
A 38-year-old man presented to an emergency department with progressive weakness and decreased urine output after having vomited up to 20 times per day over a period of 7 days. The patient was referred to our intensive care unit…
Laboratory tests were consistent with acute kidney injury (creatinine: 5.2 mg/dl, urea: 176 mg/dl); liver function tests, coagulation tests, albumin, lipase, procalcitonin, total calcium, hemoglobin, and thyroid-stimulating hormone were normal. Leukocytes were minimally elevated (11500/μl).
We suspected a prerenal acute kidney injury and a hypochloremic metabolic alkalosis due to gastric losses of HCl and fluids. Initial management consisted of oxygen therapy to correct hypoxemia and intravenous fluid therapy with normal saline and potassium chloride. Initially, a balanced crystalloid solution was infused, and later normal saline with KCl (40 mmol/l) was used because of the higher chloride content. Metoclopramide was administered to promote gastric emptying. To prevent further gastric losses of HCl, a proton-pump inhibitor was given. The patient was put on nihil per os for 24 h.
After 24 h, a total of 4.5 l of crystalloid fluid was infused. There was no further vomiting. A repeated bedside ultrasound revealed an empty stomach. The pH was corrected to 7.49, bicarbonate was reduced to 48.6 mmol/l, base excess was 23.4, chloride was 69 mmol/l, and potassium was still low at 2.8 mmol/l. There was hypoventilation with a pCO2 of 68.4 mmHg. We noted onset of diuresis. After 72 h of fluid therapy, the acid-base and electrolyte status was normal. Creatinine had decreased to 3.5 mg/dl. Small meals were tolerated.
Heymer, p. 69-70.
Therefore, claim 1 is anticipated.
Claim 2 is directed towards a method of reducing the risk of acute kidney injury in a critically ill human patient, comprising administering to the patient a pharmaceutically acceptable salt or solvate or metoclopramide in an amount effective to reduce the risk of acute kidney injury in the patient.
As shown above, Heymer teaches that the risk of acute kidney injury can be reduced in critically ill patients having metabolic alkalosis due to severe repeated vomiting. While Heymer does not teach that the metoclopramide is a salt or solvate of metoclopramide, metoclopramide is only available as metoclopramide HCl, as shown by “Drugs@FDA, search results for metoclopramide”.
Therefore, claim 2 is anticipated.
Claim 3 is directed towards the method of claim 2, wherein the intensive care unit patient is an intensive care unit patient. Claim 8 is directed towards the method of claim 1, wherein the patient is an intensive care unit patient. As shown in the rejection of claim 1, the patient in Heymer is an intensive care unit patient. Therefore, claims 3 and 8 are anticipated.
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. As shown in the rejection of claim 1, laboratory tests were consistent with acute kidney injury (creatinine: 5.2 mg/dl, urea: 176 mg/dl).
Therefore, claim 13 is anticipated.
Claim 15 is directed towards the method of claim 1, wherein the 5HT3 targeting drug is administered by intravenous injection or infusion. As shown in the rejection of claim 1, Heymer teaches that the patient received intravenous injections and infusions, and the patient was put on nihil per os for 24 hours. While metoclopramide is available as both an intravenous injection or oral tablets (see Drugs@FDA, search for metoclopramide), it is inherent in the disclosure of Heymer that the patient received an intravenous injection because he was put on nihil per os for 24 hours.
Therefore, claim 15 is 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 13-18 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 rejection of claims 1-3, 8-11, 13-18 and 20-23 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) is maintained.
The rejection of claims 1-3, 8 and 13-19 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) is maintained.
Response to Arguments
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 Applicant is claiming almost all 5HT3 targeting drugs which are in the anti-emetic class, ondansetron, dolasetron, palonosetron, alosetron, cilansetron, tropisetron, and ramosetron, but somehow expects there to be a difference between those drugs and granisetron. These drugs are therapeutic equivalents within the same class and one of ordinary skill in the art would have a reasonable expectation of success to substitute granisetron, a 5HT3 targeting drug, with another 5HT3 targeting drug, ondansetron, to obtain similar results.
Reiterated Rejection
Claims 1-3, 8, and 13-18 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 reducing mortality or increasing survival in a human patients having an acute kidney injury, 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 mortality or increase survival of 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.
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 1 was prima facie obvious at the time of filing.
Claim 2 is directed towards a method of reducing the risk of acute kidney injury in a critically ill human patient, comprising administering to the patient a pharmaceutically acceptable salt or solvate or ondansetron in an amount effective to reduce the risk of acute kidney injury in the 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, and reduce the risk of acute kidney injury 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.
Furthermore Aapro shows that both granisetron and ondansetron are on the market as pharmaceutical salts (Refs. 43 and 121) and as such one of ordinary skill in the art would have a reasonable expectation of success to use these forms.
Therefore, claims 2-3 and 8 were 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.
Claims 1-3, 8-11, 13-18 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 13-18 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 13-18 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 reducing mortality or increasing survival in a huamn 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 reduce mortality or increase survival 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.
Claim Rejections – 35 USC § 103 – New Grounds of Rejection Necessitated by Amendment
Claims 1-3, 8 and 13-19 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 13-18 above, and further in view of Liu et al. (J Thorac Dis 2019;11(4):1589-1596).
The rejection of claims 1-3, 8 and 13-18 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; heparin; metoprolol; 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 metoprolol because it is commonly known in the art that metoprolol can also reduce the risk of acute kidney injury and associated mortality.
For example, Liu teaches that metoprolol can reduce the risk of AKI and associated mortality in myocardial infarction patients:
Background
Contrast-induced acute kidney injury (CI-AKI) is a common complication of coronary angiography (CAG), which is associated with worse prognosis. Some studies indicated β-blockers could preserve renal function among patients with acute myocardial infarction (AMI), but the relationship between β-blockers and CI-AKI has not been well documented among patients with AMI who were undergoing CAG or percutaneous coronary intervention (PCI).
Methods
In this prospective, observational study, 1,309 AMI patients who were undergoing CAG or PCI were consecutively recruited between January 2010 and December 2013. Patients were assigned into β-blockers group (n=1,074) or non-β-blockers group (n=235) according to use or non-use of β-blockers (including metoprolol tartrate/metoprolol succinate/Bisoprolol Fumarate) within 24 hours of perioperative period. CI-AKI was defined as an absolute increase of >0.5 mg/dL from baseline serum creatinine (SCr) within 48–72 hours after contrast medium (CM) exposure.
Results
The overall incidence of CI-AKI was 247/1,309 (18.9%).After multivariate adjusting, a total of 10 variables were related to CI-AKI, including β-blockers [β-blockers group vs. non-β-blockers group: odds ratio (OR) =0.520; 95% confidence interval (CI), 0.291–0.930; P=0.027], age, diabetes mellitus, estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, left ventricular ejection fraction (LVEF) <40%, use of intra-aortic balloon pump (IABP), peri-hypotension, emergent PCI, coronary lesions and CM dose >200 mL. During the mean follow-up of 2.35±0.99 years, the β-blockers group was significantly associated with lower rates of mortality [β-blockers group vs. non-β-blockers group: adjusted hazard ratio (HR) =0.43; 95% CI, 0.27–0.71; P=0.001] among patients with AMI.
Conclusions
Use of β-blockers within 24 hours of perioperative period may be associated with lower rates of CI-AKI and long-term mortality among patients with AMI who are undergoing CAG or PCI.
Liu, Abstract (emphasis added).
It is prima facie obvious to combine two therapeutics known for the same purpose:
"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.
Claims 1-3, 8, 13-18 and 24 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 13-18 above, and further in view of Tampe et al. (Kidney International, Volume 91, Issue 1, January 2017, Pages 157-176).
The rejection of claims 1-3, 8 and 13-18 as obvious over Chen in view of Aapro is incorporated herein by reference.
Claim 24 is directed towards the method of claim 1, further comprising administering to the patient one or more of lisinopril; furosemide; 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 hydralazine because it is commonly known in the art that hydralazine can prevent complications associated with acute kidney injury.
For example, Tampe teaches that hydralazine can prevent the kidney fibrosis, the progression of acute-kidney-disease to chronic-kidney disease and preserve renal function:
Acute kidney injury (AKI) and progressive chronic kidney disease (CKD) are intrinsically tied syndromes. In this regard, the acutely injured kidney often does not achieve its full regenerative capacity and AKI directly transitions into progressive CKD associated with tubulointerstitial fibrosis. Underlying mechanisms of such AKI-to-CKD progression are still incompletely understood and specific therapeutic interventions are still elusive. Because epigenetic modifications play a role in maintaining tissue fibrosis, we used a murine model of ischemia-reperfusion injury to determine whether aberrant promoter methylation of RASAL1 contributes causally to the switch between physiological regeneration and tubulointerstitial fibrogenesis, a hallmark of AKI-to-CKD progression. It is known that the antihypertensive drug hydralazine has demethylating activity, and that its optimum demethylating activity occurs at concentrations below blood pressure–lowering doses. Administration of low-dose hydralazine effectively induced expression of hydroxylase TET3, which catalyzed RASAL1 hydroxymethylation and subsequent RASAL1 promoter demethylation. Hydralazine-induced CpG promoter demethylation subsequently attenuated renal fibrosis and preserved excretory renal function independent of its blood pressure–lowering effects. In comparison, RASAL1 demethylation and inhibition of tubulointerstitial fibrosis was not detected upon administration of the angiotensin-converting enzyme inhibitor Ramipril in this model. Thus, RASAL1 promoter methylation and subsequent transcriptional RASAL1 suppression plays a causal role in AKI-to-CKD progression.
Tampe, Abstract (emphasis added).
Therefore, claim 24 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.
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 extension fee 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 date of this final action.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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