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 .
Claim Status
Claims 1, 3-5, 10-18, and 21-38 are pending.
Claims 1, 10-12, 14-16, 18, and 21-22 are currently amended.
Claims 2, 6-9, and 19-20 are cancelled.
Claims 3 and 23-30 are withdrawn of record as being directed to a non-elected species. The claim examination was based on the merit for a limitation “at least two serum creatinine (SCr) values < 1.5 mg/dL are obtained from the patient 2 hours apart”. However, the limitation is omitted from the new claims 31-38 in filing RCE response. If claims 31-38 were filed early, the examiner would have requested method species election. Thus, new claims 31-38 are further withdrawn.
Claims 1, 4-5, 10-18, and 21-22 have been examined.
Priority
This application is a CON of 16/669,151 10/30/2019 ABN
16/669,151 is a CIP of 16/411,944 05/14/2019 ABN
16/411,944 is a DIV of 14/920,392 10/22/2015 PAT 10335452
14/920,392 has PRO 62/151,384 04/22/2015
14/920,392 has PRO 62/068,357 10/24/2014
The limitation “at least two serum creatinine (SCr) values ≤1.5 mg/dl are obtained from the patient 2 hours apart” was first disclosed in 16/669,151; thus, the prior art date of this application is 10/30/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 7/21/2025 and 9/30/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Modified Rejection
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 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.
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 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.
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.
1. Claims 1, 4-5, 10-11, 13-18, and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Jamil et al. (US 2016/0113994 A1) in view of Frohlich et al. (Journal of Critical Care (2012) 27, 744.e1-744.e5) and evidenced by NCT02770716 (Version 11, available to the public 2018-03-20).
Claim 1 is drawn to a method of treating a patient with type-1 hepatorenal syndrome comprising:
measuring a baseline serum creatinine level in the blood of the patient prior to administration or on day 1 of administration of terlipressin;
administering a dosage of terlipressin every 6 hours as an IV to the patient for an initial 1 to 4 days;
measuring the patient's serum creatinine level during administration;
comparing the serum creatinine level during the initial 1 to 4 days of terlipressin administration to the baseline serum creatinine level;
discontinuing administration of the dosage of terlipressin to the patient if the serum creatinine level during the initial 1 to 4 days of terlipressin administration is at or above the baseline serum creatinine level; and
continuing administration of terlipressin to the patient if the serum creatinine level of the patient during the initial 1 to 4 days of terlipressin administration is below the baseline serum creatinine level until at least two serum creatinine (SCr) values ≤ 1.5 mg/dL are obtained from the patient 2 hours apart.
Jamil et al. teach a method of treating patients with hepatorenal syndrome type I (Title).
With respect to step (a), Jamil et al. teach determining/measuring a baseline serum creatinine level for the first patient within 2 days prior to starting the administration of terlipressin [0051].
With respect to step (b), Jamil et al. teach terlipressin administered to a patient over a 4 hour to 6 hour period is in the range of 0.5 mg to about 2.0 mg [0031,0048]. Jamil et al. further teach hepatorenal syndrome type I is the development of acute kidney failure in patients known in the background art [0003].
With respect to step (c), Jamil et al. teach measuring a patient's serum creatinine level after treatment has begun and observing that the serum creatinine level in the blood of the patient decreased upon treatment with terlipressin [0032, 0070].
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With respect to steps (d) and (e), Jamil et al. teach comparing the patient’s SCr level during the 1 to 4 days of terlipressin administration and determining if the patient has a reduction in SCr level by the end of the 1 to 4 days of terlipressin administration [0124], reading on step (d). Jamil et al. teach discontinuing administration of terlipressin to the first patient if the first patient does not show a reduction in SCr level during the initial 1 to 4 days of treatment [0033], reading on step (e) shown in figure 1 as follows.
With respect to step (a part of f), Jamil et al. teach continuous administration of terlipressin to the patient for an additional 3 to 12 days if the first patient shows a reduction in SCr level during the initial 1 to 4 days [0034] and figure 1 shown as above.
Jamil et al. do not explicitly teach terlipressin treatment until at least two serum creatinine (SCr) values ≤ 1.5 mg/dL are obtained from the patient 2 hours apart.
Frohlich et al. teach creatinine clearance (Circle) is the theoretical volume of blood plasma from which all creatinine is removed per minute and represents an indirect measurement of glomerular filtration rate (GFR) as renal function indicator. Frohlich et al. teach the less cumbersome 2h-CrCl provides an equally valid, or superior estimation of GFR as the more cumbersome 24-hour measurement (744.e4, col 1, last para), suggesting that the beneficial use of 2-hour time window to help predict successful discontinuation from continuous renal therapy (744e5, col 1, para 2). NCT02770716 (Version 11) is further cited as evidence to show “two consecutive serum creatinine (SCr) values ≤ 1.5 mg/dL are obtained from the patient 2 hours apart during terlipressin treatment” (p7, last para, Primary Outcome Measurements) was common knowledge known in the art and accepted by FDA for clinical trials of terlipressin. Because Frohlich et al. and evidenced by NCT02770716 (Version 11) teach renal function with creatinine clearance (reduction of serum creatinine) can be beneficially determined by as short as 2 hours instead of 24 hours, one of ordinary skill in the art would have been taught and/or motivated by determining/measuring two serum creatinine (SCr) values ≤ 1.5 mg/dL from the patient 2 hours apart instead of 24 hours, reading on the step (f).
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine Jamil’s method of treating hepatorenal syndrome with Frohlich’s teaching of 2-hour time window of renal function (creatinine clearance) because (a) Jamil et al. teach administration of terlipressin to the patient may be continued until at least one SCr value of < 1.5 mg/dL is obtained [0053] and (b) Frohlich et al. suggest beneficial use of 2-hour creatinine clearance as a clinical indicator for renal function without a long waiting period and unnecessary treatment (744e5, col 1, para 2). NCT02770716 (Version 11) is further cited as evidence to show “two consecutive serum creatinine (SCr) values ≤ 1.5 mg/dL are obtained from the patient 2 hours apart during terlipressin treatment” (p7, last para, Primary Outcome Measurements) was common knowledge known in the art and accepted by FDA for clinical trials of terlipressin. The combination would have reasonable expectation of success because all references teach the use of serum creatinine as a clinical indicator of renal function during treatment.
With respect to claim 4, Jamil et al. teach the treated patient exhibiting at least two out of three criteria for SIRS (i)-(iii) as claimed [0090].
With respect to claim 5, Jamil et al. teach terlipressin administered to a patient over a 4 hour to 6 hour period is in the range of 0.5 mg to about 2.0 mg [0031,0048]. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I).
With respect to claim 10, Jamil et al. teach the method of terlipressin treatment further comprising 1 gram albumin per 1 kg of patient weight up to a maximum of 100 g per day of albumin to a patient [00120].
With respect to claim 11, Jamil et al. teach if on day 4 of therapy (after a minimum of 10 doses), SCr had decreased, but by less than 30% from the baseline value, the dose may be increased to 2 mg every 6 hours [0098].
With respect to claims 13-14, Jamil et al. teach the treatment providing reversal of one or more complicating factors, such as vasodilation, and reduces mortality from the associated complications within a 90 day window starting with treatment [0096].
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With respect to claims 15-18, Jamil et al. show the benefit of terlipressin treatment to improve overall survival at day 90 for transplant-free patients with hepatorenal syndrome type I (Fig. 3).
With respect to claim 21, Jamil et al. show the patient has end-stage liver disease [Fig 1, 0038].
With respect to claim 22, Jamil et al. Jamil et al. teach continuous terlipressin treatment up to 14 days [0164].
Applicant’s Arguments
There is no prima facie case of obviousness because neither Jamil nor Frohlich, either alone or in combination, teach all of the elements of the claims because (First) Frohlich contains no disclosure regarding ceasing administration of terlipressin-or any other active pharmaceutical ingredient-after two SCr values ≤ 1.5 mg/dL are obtained from the blood/serum of the patient 2 hours apart (Remarks, p11, last two para to p12, para 1-2) and (Second) Frohlich teaches away from use of serum creatinine as a successful predictor of cessation of a drug (Remarks, p12, last para to p14, para 1).
Response to Arguments
Applicant's arguments filed 9/30/2025 have been fully considered but they are not persuasive for the reasons as follows.
Applicant’s First argument is not persuasive because applicant argues a single reference of Frohlich et al. alone whereas the modified rejection is based on Jamil et al. in view of Frohlich et al. and evidenced by NCT02770716 (Version 11). Frohlich et al. teach creatinine clearance (Circle) is the theoretical volume of blood plasma from which all creatinine is removed per minute and represents an indirect measurement of glomerular filtration rate (GFR) as renal function indicator. Frohlich et al. teach the less cumbersome 2h-CrCl provides an equally valid, or superior estimation of GFR as the more cumbersome 24-hour measurement (744.e4, col 1, last para) and (b) Jamil et al. teach administration of terlipressin for treatment of impaired renal function associated with end-stage liver disease [0038]. Thus, one of ordinary skill in the art would have found it obvious for beneficial use of 2-hour creatinine clearance as a clinical indicator for renal function without a long waiting period and unnecessary treatment (744e5, col 1, para 2). NCT02770716 (Version 11) is further cited as evidence to show “two consecutive serum creatinine (SCr) values ≤ 1.5 mg/dL are obtained from the patient 2 hours apart during terlipressin treatment” (p7, last para, Primary Outcome Measurements) was common knowledge known in the art and accepted by FDA for clinical trials of terlipressin. It is noted that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091,231 USPQ 375 (Fed. Cir. 1986).
Applicant’s Second argument is not persuasive because there is no evidence Frohlich’s teaching away as argued by applicant. Frohlich et al. teach creatinine clearance (Circle) is the theoretical volume of blood plasma from which all creatinine is removed per minute and represents an indirect measurement of glomerular filtration rate (GFR) as renal function indicator. Frohlich et al. teach the less cumbersome 2h-CrCl provides an equally valid, or superior estimation of GFR as the more cumbersome 24-hour measurement (744.e4, col 1, last para). Frohlich et al. do not teach or suggest that 2-hr time window CANNOT be used to represent renal function during terlipressin treatment. Furthermore, NCT02770716 (Version 11) is further cited as evidence to show “two consecutive serum creatinine (SCr) values ≤ 1.5 mg/dL are obtained from the patient 2 hours apart during terlipressin treatment” (p7, last para, Primary Outcome Measurements) was common knowledge known in the art and accepted by FDA for clinical trials of terlipressin. Therefore, there is no evidence Frohlich’s teaching away as argued by applicant.
New Ground of rejection necessitated by amendment to claim 12.
2. Claims 1, 4-5, 10-12, 13-18, and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Jamil et al. in view of Frohlich et al. and evidenced by NCT02770716 as applied to claims 1, 4-5, 10-11, 13-18, and 21-22 and further in view of Lucassen (Product Information. Ikaria, Inc. 2012).
Claim 12 is drawn to administration of terlipressin at the dose of 1.7 mg.
Jamil et al. teach if on day 4 of therapy (after a minimum of 10 doses), SCr had decreased, but by less than 30% from the baseline value, the dose of administered terlipressin may be increased [0098].
Jamil et al. in view of Frohlich et al. and evidenced by NCT02770716 do not explicitly teach increased terlipressin at 1.7 mg.
Similarly, to Jamil et al., Lucassen teaches terlipressin (synonym of Lucassen) is effective and safe to improve renal function in patients with hepatorenal syndrome type 1 (HRS-1) in clinical trials (p2, last para; p3, Fig 1) in adult patients ranged from 23 to 74 years old (p3, para 1). Lucassen teaches formulation of terlipressin comprises mannitol, 0.85 mg terlipressin free base and salt of acetic acid reconstituted with 5 ml of 0.9% sodium chloride prior to intravenous administration (p1, Description). Lucassen further teaches the recommended starting dose is one vial of LUCASSIN (0.85 mg terlipressin) every 6 hours by slow intravenous bolus injection. If serum creatinine (SCr) has not decreased by at least 30% from the baseline value after 3 days, the dose can be increased to two vials of LUCASSIN (1.7 mg terlipressin) every 6 hours (p11, Dosage and Administration, para 1), further reading on claim 11 and the amended claim 12.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (i) Jamil et al. in view of Frohlich et al. and evidenced by NCT02770716 and (ii) Lucassen because (a) Jamil et al. teach if on day 4 of terlipressin therapy (after a minimum of 10 doses), SCr had decreased, but by less than 30% from the baseline value, the dose may be increased [0098] and (b) Lucassen further teaches the recommended starting dose is one vial of LUCASSIN (0.85 mg terlipressin) every 6 hours by slow intravenous bolus injection. If serum creatinine (SCr) has not decreased by at least 30% from the baseline value after 3 days, the dose can be increased to two vials of LUCASSIN (1.7 mg terlipressin) every 6 hours (p11, Dosage and Administration, para 1). The combination would have reasonable expectation of success because both Jamil et al. and LUCASSIN teach increase the administered dosage of terlipressin if serum creatinine (SCr) has not decreased by at least 30% from the baseline value after 3 days of terlipressin treatment.
Response to Arguments
Applicant's arguments filed 9/30/2025 have been fully considered but they are not persuasive. See response to arguments above.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/J.L/Examiner, Art Unit 1658 21-December-2025
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654