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 9-12, 16-17, 19-20, 24, 27-28, and 30-48 are pending.
Claims 9, 12, 17, 19-20, 24, 28, 30-32 are amended. Claims 33-48 are new.
Claims 1-8, 13-15, 18, 21-23, 25-26, and 29 are canceled.
Claims 9-12, 16-17, 19-20, 24, 27-28, and 30-48 have been examined.
Priority
This application is a CON of 17/976,502 10/28/2022
17/976,502 is a CIP of 17/340,765 06/07/2021
17/340,765 is a CIP of 17/104,864 11/25/2020
17/104,864 is a CIP of 16/828,681 03/24/2020 ABN
16/828,681 is a CIP 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
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Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/16/2025 and 1/6/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Rejection
The rejection of claims 9-12, 16-17, 19-20, and 32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn because the amendment to the claims overcome the rejection.
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.
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.
1. Claims 9, 12, 16-17, 19-20, 24, 27-28, 30-45, and 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Jamil et al. (US 2016/0113994 A1, cited 7/11/2025) in view of (A) Lucassin (Ikaria, Inc. 2012, previously cited 8/24/2023), Wisniewski et al. (US 2016/0122386 A1, cited 7/11/2025), and Alwadhi et al. (Indian Pediatr. 2017; 54: 729–734, cited 7/11/2025), in view of Bota et al. (The Journal of Emergency Medicine, Vol 13, No 3, pp 305- JIJ , 1995) for teaching SpO2 level, (B) in view of Boyer et al. (Journal of Hepatology. 2011; 55: 315-321, cited 7/11/2025) for teaching SCr level, (C) in view of Ling et al. (Sci Rep. 2017; 7: 42253, cited 7/11/2025) and Alexandria et al. for teaching MELD score, and (D) in view of Rodriguez et al. (J Hepatol. 2014 May;60(5):955-61, previously cited 8/27/2024) for teaching ACLF grade.
Claim 9 is drawn to a method for improving kidney function in an adult patient with type-I hepatorenal syndrome without sepsis, septic shock, or uncontrolled infection comprising administering a dose of a composition comprising terlipressin acetate to a pre-selected patient with (A) baseline SpO2 is ≥ 90%, (B) baseline SCr is <5 mg/dL, (C) baseline MELD score is <35, and (D) baseline ACLF Grade is <3; wherein, the pre-selected patient has reduced risk of dying terlipressin treatment due to an adverse event up to 30 days post-treatment as compared to patients treated with albumin; wherein, the terlipressin treatment of pre-selected patient having a reduced risk of dying due to an adverse event up to 30 days post-treatment as compared to a patient with placebo of albumin treatment without albumin.
Jamail et al. teach method of treating patient with hepatorenal syndrome type I, HRS-1, (Title). Jamail et al. teach the treated patients at age 18 ages or older [0161], reading on an adult patient. Jamail et al. teach to avoid the unnecessary administration of drug to patients who are critically ill because of terlipressin is very effective in patients exhibiting certain criteria but is not effective in patients that do not meet this criteria. Possible warnings and precautions associated with terlipressin include ischemia. Ischemic events (cardiac, gastrointestinal, and skin) can occur following administration of terlipressin and may require temporary interruption, dose decrease, or permanent discontinuation. Since patients with HRS-1 are critically ill and terlipressin can have side-effects, to determine if a patient is likely to respond to terlipressin and only treating those patients can be extremely beneficial and even life-saving as terlipressin is known to be effective in 33-60% of HRS-1 patients. Jamail et al. teach adverse reaction in more than 10% patients included vomiting, abdominal pain, nausea, diarrhea, intestinal ischemia, dyspnea, sneezing, pulmonary edema and fluid overload known in the art. All conditions that could be severely detrimental to already fragile patients with HRS-1 [0022]. Jamail et al. further teach terlipressin treated patients without sepsis, septic shock, or uncontrolled infection [0157]. Thus, one of ordinary skill in the art would have found it obvious to (a) identify a patient likely to respond to terlipressin and only treat those pre-selected patients expected to be beneficial and even life-saving with terlipressin as well as (b) reduce the incidence of adverse events in patients administered with terlipressin by excluding patients unlikely to respond to terlipressin treatment.
With respect to obtain a baseline oxygen saturation (SpO2), Lucassin teaches Lucassin contains 0.85 mg terlipressin free base in acetate salt as a sterile, lyophilized powder for intravenous administration (p1, Description), reading on terlipressin acetate. Lucassin teaches (i) terlipressin should not be used in patients with unstable angina or recent acute myocardial infarction and (ii) ischaemic events (cardiac, gastrointestinal, and skin) have occurred following administration of terlipressin resulting in reducing blood supply to tissue causing tissue damage (defined as ischemia) and may require temporary interruption, dose decrease or permanent discontinuation of terlipressin (p6, Ischaemic Events), consistent with Jamil et al. [0022]. Common adverse events of terlipressin including fluid overload can be found in Lucassin’s Table 2 (p8), Table 3 (p9), and Table 4 (p10). Lucassin explicitly teaches terlipressin and other vasopressin analogues reduced blood flow to tissues resulting in tissue damage such as ischaemia in various tissues (p9, Table 3) due to hypoxia causing insufficient oxygen in body tissue and blood (p7, para 2) and further evidenced by Wisniewski et al. showing adverse events of hypoxia and ischemia as an adverse event of administering terlipressin known in the art [0020], consistent with Lucassin. Alwadhi et al. teach Oxygen saturation (SpO2) was measured by a pulse oximeter and a clinical predictor of hypoxia is SpO2 <90% (p729, col 1, Methods). Thus, one of ordinary skill in the art would have found it obvious to measure baseline of SpO2 and administer terlipressin only to a patient with baseline of SpO2 ≥ 90% to avoid terlipressin administration to a patient with hypoxia and/or ischemia as measured by pulse oximeter. Bota et al. teach the continuous measurement of arterial oxygen saturation using pulse oximetry (SpO2) has become popular for critically ill hospitalized patients (Abstract). Bota et al. teach this technology has the added benefit of providing a continuous and immediately available record of oxygen saturation, so that changes in oxygenation (deterioration and improvement) may be observed and acted upon (p306, col 1, para 3). Because (a) hypoxia (SpO2 <90%) and ischaemia are known adverse events of terlipressin administered every 6 hours as taught by Lucassin (p3, para 1). Thus, one of ordinary skill in the art would have found it obvious to obtain the baseline of SpO2 and only administer terlipressin to a patient with baseline SpO2 ≥ 90% to avoid administration of terlipressin to a patient with hypoxia or at risk of developing ischaemic events. Since ischaemia or hypoxia is a known adverse event caused terlipressin treatment, one of ordinary skill in the art would have found it obvious to constantly monitor SpO2 with continuous pulse oximetry before and/or after each administration of terlipressin to further avoid administration of terlipressin to a patient with hypoxia or at risk of developing ischaemic events.
With respect to obtain a baseline serum creatinine (SCr) level, Boyer et al. teach administration of terlipressin plus albumin is effective in reversing type 1 HRS as compared to albumin alone. However, only about 1 /3 of patients respond to treatment, therefore, predictors of response and survival would help identify the patients most likely to benefit from treatment (p315, col 1, Background & Aims), consistent with Jamail et al. [0022]. Boyer et al. teach the most consistent predictor of response to terlipressin and of survival is the baseline serum creatinine (SCr). Patients most likely to benefit from terlipressin have earlier onset renal failure with serum creatinine < 5.0 mg/dl (p315, col 1, Conclusions). Thus, one of ordinary skill in the art would have found it obvious to administer terlipressin only to a selected patient with baseline of SCr < 5.0 mg/dl.
With respect to obtain a baseline MELD score, Ling et al. teach MELD presented the best ability in predicting 3-month, 6-month and 1-year mortality, showing a significantly better predictive ability than UKELD and iMELD (Abstract). Ling et al. teach MELD has been validated as a good predictor of mortality for a broader range of patients with end-stage liver disease, including candidates on the waiting list for liver transplantation (p1, para 2). Ling et al. suggest MELD score can be used to analyze patients with hepatorenal syndrome (p2, Table 1; p6, Table 3). Ling et al. show MELD with great correlation with 3-month death, the lower
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MELD score the better, as follows (p5, Fig 3), suggesting a patient with lower baseline MELD score is likely to respond to terlipressin. Ling et al. further show even more benefit for survival after liver transplant with lower MEDL shown as follows (p5, Fig 2B). Because Ling et al. suggest a benefit to exclude patients with MEDL ≥ 35 to reduce rate of patient death during terlipressin treatment, it would be obvious to beneficially administer terlipressin to ONLY a patient with baseline MELD score < 35 to enhance the successful rate of treatment. Similarly,
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Alessandria et al. teach “MELD Score and Clinical Type Predict Prognosis in Hepatorenal Syndrome: Relevance to Liver Transplantation” (Title). Alessandria et al. show 3-month survival prediction of HRS is a function of MELD score (p1285, Fig 4). The lower MELD score (< 35) has a higher 3-month survival probability consistent with Ling et al. One of ordinary skill in the art would select a patient group with baseline MELD score at about 30 (less than 35) to cover both type I and type II HRS patients as taught by Alessandria et al. with predictable increase of survival rate consistent with Ling’s Figures 2B and 3.
Rodriguez et al. teach terlipressin and albumin is the standard of care for classical type-1 hepatorenal syndrome (HRS) not associated with active infections (p955, col 1, Background & Aims). Rodriguez et al. teach patients with associated severe ACLF (ACLF Grade = 3) are unlikely to respond to terlipressin treatment (p955, col 2, Conclusion; p960, col 2, para 4) shown
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as follows (p958, col 2, Table 3). Rodriguez et al. teach patients were carefully evaluated every day during treatment for early signs of side effects to terlipressin (p956, col 1, last para to col 2, para 1) consistent with Jamil et al. and Lucassin described above. Thus, one of ordinary skill in the art would have found it obvious to administer terlipressin only to a patient with baseline of ACLF grade < 3. The instant Figure 5
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shows patients with baseline ACLF grade 0-2 with or without terlipressin treatment inherently having higher survival rate than ACLF grade 3 with or without terlipressin treatment for 14 days, 30 days, 60 days and 90 days consistent with Rodriguez’s teaching.
Jamil et al. teach the use of albumin as a placebo, which is known to have no therapeutic effect of hepatorenal syndrome in comparison to terlipressin treatment [0161]. Since the pre-selected patient group with baseline SpO2 ≥ 90%, serum creatinine < 5.0 mg/dl, baseline of ACLF grade < 3, and baseline MEDL score < 35 is relatively healthy and expected to have successful response to terlipressin treatment as taught and/or suggested by the cited references, it would be obvious to expect the pre-selected patient group treated by terlipressin to have reduced risk of dying due to an adverse event up to 30 days post-treatment as compared to the placebo group of pre-selected patient group treated by albumin without the therapeutic agent of terlipressin, reading on claim 9.
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. with (ii) Lucassin in view of Wisniewski et al., Alwadhi et al. and Bota et al. because (a) Jamil et al. teach administration of terlipressin to a pre-selected patient group likely to respond to terlipressin treatment to avoid/reduce adverse events of terlipressin treatment and (b) Lucassin (see p7, para 2; Table 2-4) in view of Wisniewski et al. [0020] teach various adverse events of terlipressin treatment comprise hypoxia and/or ischemia, fluid overload. Lucassin further teach patients at risk should be closed monitored and serum creatinine levels should be monitored daily to assess response to therapy (p6, Respiratory Effects and Laboratory Monitoring), (c) Alwadhi et al. teach Oxygen saturation (SpO2) was measured by a pulse oximeter and a clinical predictor of hypoxia is SpO2 <90% (p729, col 1, Methods), and (d) Bota et al. teach the continuous measurement of arterial oxygen saturation using pulse oximetry (SpO2) has become popular for critically ill hospitalized patients (Abstract). Bota et al. teach this technology has the added benefit of providing a continuous and immediately available record of oxygen saturation, so that changes in oxygenation (deterioration and improvement) may be observed and acted upon (p306, col 1, para 3). The combination would have reasonable expectation of success because the use of continuous pulse oximetry to obtain a baseline SpO2 ≥ 90% and continuous monitoring SpO2 level in patients during terlipressin treatment is expected to increase patient’s response to terlipressin treatment with reduced risk of developing adverse events such as hypoxia, ischemia, or other known adverse events taught in Lucassin’s Table 2-4.
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 Lucassin, Wisniewski et al., Alwadhi et al. and Bota et al. and (ii) Boyer et al. because (a) Jamil et al. in view of Lucassin, Wisniewski et al., Alwadhi et al. and Bota et al. teach a method of administering terlipressin to a pre-selected patient likely to respond to terlipressin treatment with reduced risk of developing adverse events (e.g., hypoxia and ischaemia) and (b) Boyer et al. teach the most consistent predictor of response to terlipressin and of survival is the baseline serum creatinine (SCr). Patients most likely to benefit from terlipressin have earlier onset renal failure with serum creatinine < 5.0 mg/dl (p315, col 1, Conclusions). The combination would have reasonable expectation of success because the references teach administration of terlipressin to a pre-selected patient likely to respond to terlipressin treatment to increase patient’s survival rate after treatment..
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 Lucassin, Wisniewski et al., Alwadhi et al., Bota et al. Boyer et al. with (ii) Ling et al. in view of Alessandria et al. because (a) Jamil et al. in view of Lucassin, Wisniewski et al., Alwadhi et al., Bota et al., and Boyer et al. teach a method of administering terlipressin to a pre-selected patient likely to respond to terlipressin treatment with reduced risk of developing adverse events, (b) Ling et al. teach MELD has been validated as a good predictor of mortality for a broader range of patients with end-stage liver disease, including candidates on the waiting list for liver transplantation (p1, para 2) and suggest a benefit to exclude critically ill patients with MEDL ≥ 35 to reduce rate of patient death during terlipressin treatment (p5, Fig 2B and Fig 3), and (c) Alessandria et al. show 3-month survival prediction of HRS is a function of MELD score (p1285, Fig 4) and lower MELD score (< 35) has a higher 3-month survival probability consistent with Ling et al. The combination would have reasonable expectation of success because Alessandria et al. show 3-month survival prediction of HRS is a function of MELD score and lower MELD score (< 35) has a higher 3-month survival probability consistent with Ling et al.
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 Lucassin, Wisniewski et al., Alwadhi et al., Bota et al. Boyer et al., Ling et al. and Alessandria et al. with (ii) Rodriguez et al. because (a) Jamil et al. in view of Lucassin, Wisniewski et al., Alwadhi et al., Bota et al. Boyer et al., Ling et al. and Alessandria et al. teach a method of administering terlipressin to a pre-selected patient likely to respond to terlipressin treatment with reduced risk of developing adverse events and (b) Rodriguez et al. teach patients with associated severe ACLF (ACLF Grade = 3) are unlikely to respond to terlipressin treatment (p955, col 2, Conclusion; p960, col 2, para 4; p958, col 2, Table 3). Rodriguez et al. further teach patients were carefully evaluated every day during treatment for early signs of side effects to terlipressin (p956, col 1, last para to col 2, para 1) consistent with Jamil et al. and Lucassin described above. The combination would have reasonable expectation of success because the references teach administration of terlipressin to a pre-selected patient group likely to respond to terlipressin treatment to increase patient’s survival rate after treatment.
With respect to claim 12, Jamil et al. teach administration of terlipressin 1 mg intravenously every 6 hours as a slow bolus injection over 2 minutes [0164].
With respect to claims 16-17, Alwadhi et al. teach Oxygen saturation (SpO2) was measured by a pulse oximeter and a clinical predictor of hypoxia is SpO2 <90% (p729, col 1, Methods). Bota et al. teach the continuous measurement of arterial oxygen saturation using pulse oximetry (SpO2) has become popular for critically ill hospitalized patients (Abstract). Bota et al. teach this technology has the added benefit of providing a continuous and immediately available record of oxygen saturation, so that changes in oxygenation (deterioration and improvement) may be observed and acted upon (p306, col 1, para 3). It would be obvious to only administer terlipressin to patients with SpO2 ≥ 90% to avoid administration of terlipressin to a patient with hypoxia or at risk of developing ischemia and other adverse events during terlipressin treatment.
With respect to claims 19-20, Lucassin teaches fluid overload as one of common adverse event of terlipressin treatment (Table 2-4). Lucassin teaches management of suspected adverse drug reactions may require temporary interruption and/or dose reduction (p11, Dosage and Administration, para 3). Similarly, Jamil et al. suggest interruption of treatment (discontinue treatment) due to adverse event may be restart later [0098].
With respect toc alim 24, See rejection of claim 9 above.
With respect to claim 27, Jamil et al. teach administration of terlipressin 1 mg intravenously every 6 hours as a slow bolus injection over 2 minutes [0164].
With respect to claims 28 and 30-31, Lucassin explicitly teaches terlipressin and other vasopressin analogues reduced blood flow to tissues resulting in tissue damage such as ischaemia in various tissues (p9, Table 3) due to hypoxia causing insufficient oxygen in body tissue and blood (p7, para 2) and further evidenced by Wisniewski et al. showing adverse events of hypoxia and ischemia as an adverse event of administering terlipressin known in the art [0020]. Alwadhi et al. teach Oxygen saturation (SpO2) was measured by a pulse oximeter and a clinical predictor of hypoxia is SpO2 <90% (p729, col 1, Methods). Thus, one of ordinary skill in the art would have found it obvious to measure SpO2 and administer terlipressin before and during terlipressin treatment only to a patient with baseline of SpO2 ≥ 90% to avoid terlipressin administration to a patient with hypoxia and/or ischemia as measured by pulse oximeter and discontinue terlipressin administration to a patient with SpO2 < 90%. Lucassin treatment of terlipressin for a period up to 14 days (p3, para 1; Fig 1), consistent with Jamil et al. [0164].
With respect toc alim 32, See rejection of claim 9 above.
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With respect to claims 33-35, Jamil et al. show the patient's SCr level is measured 4 days after administration of the composition is started and discontinue terlipressin treatment if SCr is at or above the baseline SCr level without reduction in SCr on day 4 (Fig 1).
With respect to claim 36-38, Lucassin teaches 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).
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With respect to claim 39, Lucassin teaches treatment success at Day 14 with two serum creatinine [SCr] levels ≤132.6 μmol/L (same as 1.5 mg/dL) 48 ± 24 h apart without intervening up to Day 14 (p3, para 1-2), reading on for a maximum of 14 days consistent with Jamil [00164].
With respect claims 40-42, Lucassin teaches 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). Namely, if SCr level reduction > 30%, the dose of terlipressin treatment is continuous until two serum creatinine [SCr] levels ≤132.6 μmol/L (132.6 μmol/L same as 1.5 mg/dL) 48 ± 24 h apart without intervening up to Day 14 (p3, para 1-2).
With respect to claim 43, Lucassin teaches the recommended starting dose is one vial of LUCASSIN (0.85 mg terlipressin) every 6 hours by slow intravenous bolus injection (p11, Dosage and Administration, para 1).
With respect to claim 44, Lucassin teaches the patients treated terlipressin also treated with albumin (p3, para 1), consistent with Jamil et al. [0085].
With respect to claim 45 and 47-48, Jamail et al. teach adverse reaction in more than 10% patients included vomiting, abdominal pain, nausea, diarrhea, intestinal ischemia, dyspnea, sneezing, pulmonary edema and fluid overload known in the art. All conditions that could be severely detrimental to already fragile patients with HRS-1 [0022]. Lucassin teaches fluid overload as one of common adverse event of terlipressin treatment (Table 2-4). Lucassin teaches management of suspected adverse drug reactions may require temporary interruption (discontinue treatment) and/or dose reduction (p11, Dosage and Administration, para 3). Similarly, Jamil et al. suggest interruption of treatment (discontinue treatment) due to adverse event may be restart later [0098]. Thus, it would be obvious to monitor adverse event of fluid overload and discontinue the treatment if the patient experiences fluid overload, reading on claim45 and 47. Furthermore, it would be obvious to continuously administer terlipressin and albumin if the patient does not experience adverse of fluid overload, reading on claim 48.
Applicant’s Arguments
First, there is no prima facie case of obviousness because none of the nine (9) references cited by the Examiner, either alone or in combination, teach all of the elements of the claims (Remarks, p9, para 2-3).
Second, none of the cited references would have provided a person skilled in the art (hereafter, "POSA") with a motivation to limit the HRS-1 patient population treated with
terlipressin to only patients with a MELD score < 35, a serum creatinine level < 5 mg/dL, or an ACLF Grade< 3 to prevent the increased mortality associated with terlipressin treatment (Remarks, p9, last para to p17, para 1).
Third, arguendo, even if Rodriguez taught the claimed ACLF grade limitation, Boyert taught the claimed serum creatinine level, and Ling taught the claimed MELD score-which they
do not as explained above-a POSA would not have been motivated to combine these references
with a reasonable expectation of success because at least Boyert, Rodriguez, and Wisniewski teach away from their combination (Remarks, p17, para 2 to p19, para 1).
Secondary consideration
Unexpected Result (p21, last para to p26, para 1)
Long-Felt Unmet Need (p26, para 2 to p32, para 2).
Response to Arguments
Applicant's arguments filed 1/9/2026 have been fully considered but they are not persuasive because the arguments do not apply to the modified rejection based on Jamil et al. (US 2016/0113994 A1, cited 7/11/2025) in view of (A) Lucassin (Ikaria, Inc. 2012, previously cited 8/24/2023), Wisniewski et al. (US 2016/0122386 A1, cited 7/11/2025), and Alwadhi et al. (Indian Pediatr. 2017; 54: 729–734, cited 7/11/2025), in view of Bota et al. (The Journal of Emergency Medicine, Vol 13, No 3, pp 305- JIJ , 1995) for teaching SpO2 level, (B) in view of Boyer et al. (Journal of Hepatology. 2011; 55: 315-321, cited 7/11/2025) for teaching SCr level, (C) in view of Ling et al. (Sci Rep. 2017; 7: 42253, cited 7/11/2025) and Alexandria et al. for teaching MELD score, and (D) in view of Rodriguez et al. (J Hepatol. 2014 May;60(5):955-61, previously cited 8/27/2024) for teaching ACLF grade.
Applicant’s first argument is not persuasive. In particular, Jamail et al. further teach terlipressin treated patients without sepsis, septic shock, or uncontrolled infection [0157], which is the amendment to the base claim 9. Furthermore, Ling et al. teach the Model for End-stage Liver Disease (MELD) scoring system was developed to estimate the survival of patients undergoing transjugular intrahepatic portosystemic shunts. It has been validated as a good predictor of mortality for a broader range of patients with end-stage liver disease, including candidates on the waiting list for liver transplantation (p1, para 2). Alessandria et al. show 3-month survival prediction of HRS is a function of MELD score (p1285, Fig 4). The lower MELD score (< 35) has a higher 3-month survival probability consistent with Ling et al. Lastly, applicant’s opinions of the amended claims are not prima facie obvious to the combined prior art teachings based on narrowly interpreting and arguing individual prior art teachings separately, not knowledge, skill, and ability of an ordinary skill in the art defined in MPEP 2141.03 (I) as “A person of ordinary creativity able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at ___, 82 USPQ2d at 1396.” Also see the modified rejection above in details and reasons to combine the references have been described above not repeated here.
Applicant’s first argument is not persuasive because the modified rejection based on Jamil et al. (US 2016/0113994 A1, cited 7/11/2025) in view of (A) Lucassin (Ikaria, Inc. 2012, previously cited 8/24/2023), Wisniewski et al. (US 2016/0122386 A1, cited 7/11/2025), and Alwadhi et al. (Indian Pediatr. 2017; 54: 729–734, cited 7/11/2025), in view of Bota et al. (The Journal of Emergency Medicine, Vol 13, No 3, pp 305- JIJ , 1995) for teaching SpO2 level, (B) in view of Boyer et al. (Journal of Hepatology. 2011; 55: 315-321, cited 7/11/2025) for teaching SCr level, (C) in view of Ling et al. (Sci Rep. 2017; 7: 42253, cited 7/11/2025) and Alexandria et al. for teaching MELD score, and (D) in view of Rodriguez et al. (J Hepatol. 2014 May;60(5):955-61, previously cited 8/27/2024) for teaching ACLF grade. The cited references teach a preferred patient group likely to respond to terlipressin treatment to increase the probability of treatment success and survival rate of patients as well as reduce known adverse events of terlipressin treatment. See the rejection described above not repeated here.
Applicant’s second argument is not persuasive. The cited references above teach and/or suggest a preferred patient group with clinical indicators of SpO2 ≥ 90%, a MELD score < 35, a serum creatinine level < 5 mg/dL, or an ACLF Grade< 3 relevant to effective response to terlipressin treatment and the reasons to combined the cited references have been described in the rejection above not repeated here. "Expected beneficial results are evidence of obviousness of a claimed invention. See MPEP 716.02(c)(II).
Applicant’s third argument is not persuasive. The cited references teach a preferred patient group likely to respond to terlipressin treatment to increase the probability of success treatment and survival rate as well as reduce known adverse events of terlipressin treatment described above not repeated here. Applicant argues no explicit teaching to combine the references; thus, the references teach away from this invention. In contrast, the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See MPEP 2144. None of the references teach “Terlipressin CANNOT be used to treat hepatorenal syndrome”; thus, the examiner did not find any evidence of a cited reference teaching away from this invention as argued by applicant. Furthermore, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). See MPEP 2123(II). Thus, the argument of Wisniewski teaching away this invention (Remarks, p18, last para to p19., para 1) is not persuasive.
Applicant’s arguments of Secondary Consideration are not persuasive for the reasons as follows.
The arguments of unexpected result are not persuasive because there is no unexpected result for administration of terlipressin to treat a pre-selected patient group likely to respond to terlipressin treatment to increase patient’s survival after treatment as taught by the combined references. The cited prior art references teach and/or suggest patients with certain clinical indicators (SpO2 ≥ 90%, MELD score < 35, a serum creatinine level < 5 mg/dL, or an ACLF Grade< 3) are likely to respond to terlipressin treatment with expected success described above not repeated here. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). See MPEP 716.02(b).
The arguments of Long-Felt Unmet need is not persuasive because of the following reasons.
Jamil et al. teach the only effective and permanent treatment for end-stage cirrhosis and HRS is liver transplantation [0037] demonstrating the long-felt need recognized in the art is lack of sufficient liver organs for transplantation as a permanent treatment. Further evidenced by Jamil’s teaching of “Unfortunately, patients with HRS Type-1 may die from renal failure while waiting for a liver transplant.” [0003]
The cited prior art references teach and/or suggest administration of terlipressin to a pre-selected patient group with clinical indicators (SpO2 ≥ 90%, MELD score < 35, a serum creatinine level < 5 mg/dL, or an ACLF Grade< 3) likely to respond to terlipressin treatment with reduced risk of developing adverse events to extend survival of the pre-selected patients, waiting for liver transplantation, after terlipressin treatment. See all the response to arguments and the modified rejection above in details.
2. Claims 9-12, 16-17, 19-20, 24, 27-28, 30-45, and 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, and (D) Rodriguez et al. for teaching ACLF grade as applied to claims 9, 12, 16-17, 19-20, 24, 27-28, 30-45, 47-48, and further in view of NCT02770716 (Last updated posted 2019-08-14, referred as NCT02770716-2019, cited 7/17/2025).
Claims 10-11 are directed to the terlipressin composition comprising 1 mg terlipressin acetate and 10 mg mannitol.
Lucassin teach a terlipressin composition comprising 0.85 mg terlipressin free base with mannitol and acetate salt as a sterile, lyophilized powder for reconstitution with 5 ml of 0.9% sodium chloride (p1, Description). Jamil et al. teach the terlipressin composition comprising 1 mg active ingredient and 10 mg mannitol [0020].
Jamil et al. in view of Lucassin did not specify the 1 mg active ingredient as 1 mg terlipressin acetate.
Similarly, NCT02770716-2019 teaches “Study To Confirm Efficacy and Safety of Terlipressin in Hepatorenal Syndrome (HRS) Type 1” (Title)”. NCT02770716-2019 teaches administration of a composition comprising 1 mg active ingredient of terlipressin acetate and 10 mg mannitol in 5 ml of sterile 0.9% sodium chloride solution for intravenous bolus injection over 2 minutes every 6 hours to treat patients with hepatorenal syndrome (p7, Arms and Interventions) consistent with Jamil et al. and Lucassin. NCT02770716-2019 further teaches HRS Reversal defined as 2 consecutive qualified SCr values ≤ 1.5 mg/dl at least 2 hours apart (p7, Primary Outcome Measures # 1).
Because NCT02770716-2019 teaches beneficial administration of 1 mg active ingredient of terlipressin acetate and 10 mg mannitol to treat a patient with type-I hepatorenal syndrome, one of ordinary skill in the art would have found it obvious to administer 1 mg active ingredient of terlipressin acetate and 10 mg mannitol to treat type-I hepatorenal syndrome consistent with Jamil et al. and Lucassin, reading on claims 10-11.
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 Lucassin, Wisniewski et al., Alwadhi et al., Bota et al. Boyer et al., Ling et al., Alessandria et al. and Rodriguez et al. with (ii) NCT02770716-2019 because (a) Jamil et al. in view of Lucassin, Wisniewski et al., Alwadhi et al., Bota et al. Boyer et al., Ling et al., Alessandria et al. and Rodriguez et al. teach administration of 1 mg terlipressin active ingredient and 10 mg mannitol to treat pre-selected patients with type-I hepatorenal syndrome (Lucassin p1, Description; Jamil et al. [0020]) and (b) NCT02770716-2019 teaches administration of a composition comprising 1 mg active ingredient of terlipressin acetate and 10 mg mannitol in 5 ml of sterile 0.9% sodium chloride solution for intravenous bolus injection over 2 minutes every 6 hours to treat patients with hepatorenal syndrome (p7, Arms and Interventions) consistent with Jamil et al. and Lucassin. The combination would have reasonable expectation of success because all Jamil et al., Lucassin, and NCT02770716-2019 teach administration of terlipressin as an active ingredient to treat patients with type-I hepatorenal syndrome.
Response to Arguments
Applicant's arguments filed 1/9/2026 have been fully considered but they are not persuasive. See response to arguments above.
3. Claims 9, 12, 16-17, 19-20, 24, 27-28, and 30-48 are rejected under 35 U.S.C. 103 as being unpatentable over Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, and (D) Rodriguez et al. for teaching ACLF grade as applied to claims 9, 12, 16-17, 19-20, 24, 27-28, 30-45, 47-48, and further in view of Pulimood et al. (Crit Care 2000, 4:151–155).
Claim 46 is drawn to the patient experiences fluid overload and administration of the albumin is discontinued.
Jamil et al. in view of Lucassin, Wisniewski et al., Alwadhi et al., Bota et al. Boyer et al., Ling et al., Alessandria et al. and Rodriguez et al. teach fluid overload as an adverse event of terlipressin treatment. Lucassin disclosed intravenous albumin for plasma volume expansion (p3, para 1).
Jamil et al. in view of Lucassin, Wisniewski et al., Alwadhi et al., Bota et al. Boyer et al., Ling et al., Alessandria et al. and Rodriguez et al. do not specify discontinuation of albumin administration to a patient with fluid overload.
Pulimood et al. teach administration of albumin can result in fluid overload (p153, col 1, para 2) and further suggest death with albumin might be fluid overload (p154, col 2, para 1). Because albumin can cause fluid overload leading to death, one of ordinary skill in the art would have found it obvious to discontinue administration of albumin after the patient experiences fluid overload, reading on claim 46.
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 Lucassin, Wisniewski et al., Alwadhi et al., Bota et al. Boyer et al., Ling et al., Alessandria et al. and Rodriguez et al. with (ii) Pulimood et al. because (a) Jamil et al. in view of Lucassin, Wisniewski et al., Alwadhi et al., Bota et al. Boyer et al., Ling et al., Alessandria et al. and Rodriguez et al. teach fluid overload as an adverse event of terlipressin treatment. Lucassin disclosed intravenous albumin for plasma volume expansion (p3, para 1) and (b) Pulimood et al. teach administration of albumin can result in fluid overload (p153, col 1, para 2) and further suggest death with albumin might be fluid overload (p154, col 2, para 1). The combination would have reasonable expectation of success because discontinuation of albumin administration is able to eliminate albumin-mediated fluid overload and death in patients.
Response to Arguments
Applicant's arguments filed 1/9/2026 have been fully considered but they are not persuasive. See response to arguments above.
Modified Rejection
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 9-12, 16-17, 19-20, 24, 27-28, 30-45, and 47-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 22 of copending Application No. 19/213,363 (the ‘363 application) in view of Jamil et al. (US 2016/0113994 A1, cited 7/11/2025) in view of (A) Lucassin (Ikaria, Inc. 2012, previously cited 8/24/2023), Wisniewski et al. (US 2016/0122386 A1, cited 7/11/2025), and Alwadhi et al. (Indian Pediatr. 2017; 54: 729–734, cited 7/11/2025), in view of Bota et al. (The Journal of Emergency Medicine, Vol 13, No 3, pp 305- JIJ , 1995) for teaching SpO2 level, (B) in view of Boyer et al. (Journal of Hepatology. 2011; 55: 315-321, cited 7/11/2025) for teaching SCr level, (C) in view of Ling et al. (Sci Rep. 2017; 7: 42253, cited 7/11/2025) and Alexandria et al. for teaching MELD score, (D) in view of Rodriguez et al. (J Hepatol. 2014 May;60(5):955-61, previously cited 8/27/2024) for teaching ACLF grade, and NCT02770716 (Last updated posted 2019-08-14, referred as NCT02770716-2019, previously cited).
Claim 22 of the ‘363 application disclosed a method of treating type-1 hepatorenal syndrome comprising administering terlipressin to a patient with baseline MELD score < 35, a serum creatinine level < 5 mg/dL, or an ACLF Grade< 3.
Claim 22 of the ‘363 application dis not disclosed a patient’s baseline level of SpO2.
The relevancy of Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, and (D) Rodriguez et al. for teaching ACLF grade and further in view of NCT02770716 as applied to claims 9-12, 16-17, 19-20, 24, 27-28, 30-45, and 47-48 not repeated here.
Because Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, and (D) Rodriguez et al. for teaching ACLF grade and further in view of NCT02770716 teach beneficial administration of terlipressin to a pre-selected patient with clinical indicators of MELD score < 35, a serum creatinine level < 5 mg/dL, or an ACLF Grade< 3 taught by claim 22 of the ‘363 application are likely to respond to terlipressin treatment, one of ordinary skill in the art would have found it obvious to beneficially combine claim 22 of the ‘363 application and Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, (D) Rodriguez et al. for teaching ACLF grade and (E) NCT02770716 to treat a pre-selected patient group with clinical indicators of baseline SpO2 ≥ 90%, MELD score < 35, a serum creatinine level < 5 mg/dL, and an ACLF Grade< 3.
Thus, claim 22 of the ‘363 application and Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, (D) Rodriguez et al. for teaching ACLF grade and (E) NCT02770716 are obvious to the instant claims 9-12, 16-17, 19-20, 24, 27-28, 30-45, and 47-48.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 1/9/2026 have been fully considered but they are not persuasive because the request of this rejection held in abeyance until all other rejections have been overcome does not overcome this provisional rejection.
Claims 9-12, 16-17, 19-20, 24, 27-28, 30-45, and 47-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/244,769 (the ‘769 application) in view of Jamil et al. (US 2016/0113994 A1, cited 7/11/2025) in view of (A) Lucassin (Ikaria, Inc. 2012, previously cited 8/24/2023), Wisniewski et al. (US 2016/0122386 A1, cited 7/11/2025), and Alwadhi et al. (Indian Pediatr. 2017; 54: 729–734, cited 7/11/2025), in view of Bota et al. (The Journal of Emergency Medicine, Vol 13, No 3, pp 305- JIJ , 1995) for teaching SpO2 level, (B) in view of Boyer et al. (Journal of Hepatology. 2011; 55: 315-321, cited 7/11/2025) for teaching SCr level, (C) in view of Ling et al. (Sci Rep. 2017; 7: 42253, cited 7/11/2025) and Alexandria et al. for teaching MELD score, (D) in view of Rodriguez et al. (J Hepatol. 2014 May;60(5):955-61, previously cited 8/27/2024) for teaching ACLF grade, and NCT02770716 (Last updated posted 2019-08-14, referred as NCT02770716-2019, previously cited).
Claim 1 of the ‘769 application disclosed a formulation of terlipressin acetate with molecular formula C52H74N16O15S2•(C2H4O2)n and n is between 1.0 to 3.5.
Claim 1 of the ‘769 application did not disclosed administration the formulation of terlipressin acetate to treat hepatorenal syndrome.
The relevancy of Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, and (D) Rodriguez et al. for teaching ACLF grade and further in view of NCT02770716 as applied to claims 9-12, 16-17, 19-20, 24, 27-28, 30-45, and 47-48 not repeated here.
Because Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, and (D) Rodriguez et al. for teaching ACLF grade and further in view of NCT02770716 teach beneficial administration of terlipressin acetate to a pre-selected patient with clinical indicators of MELD score < 35, a serum creatinine level < 5 mg/dL, or an ACLF Grade< 3 likely to respond to terlipressin treatment, one of ordinary skill in the art would have found it obvious to beneficially combine the terlipressin acetate formulation taught by claim 1 of the ‘769 application and Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, (D) Rodriguez et al. for teaching ACLF grade and (E) NCT02770716 to treat a pre-selected patient group with hepatorenal syndrome.
Thus, claim 1 of the ‘769 application and Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, (D) Rodriguez et al. for teaching ACLF grade and (E) NCT02770716 are obvious to the instant claims 9-12, 16-17, 19-20, 24, 27-28, 30-45, and 47-48.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 1/9/2026 have been fully considered but they are not persuasive because the request of this rejection held in abeyance until all other rejections have been overcome does not overcome this provisional rejection.
Claims 9-12, 16-17, 19-20, 24, 27-28, 30-45, and 47-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/244,777 (the ‘777 application) in view of Jamil et al. (US 2016/0113994 A1, cited 7/11/2025) in view of (A) Lucassin (Ikaria, Inc. 2012, previously cited 8/24/2023), Wisniewski et al. (US 2016/0122386 A1, cited 7/11/2025), and Alwadhi et al. (Indian Pediatr. 2017; 54: 729–734, cited 7/11/2025), in view of Bota et al. (The Journal of Emergency Medicine, Vol 13, No 3, pp 305- JIJ , 1995) for teaching SpO2 level, (B) in view of Boyer et al. (Journal of Hepatology. 2011; 55: 315-321, cited 7/11/2025) for teaching SCr level, (C) in view of Ling et al. (Sci Rep. 2017; 7: 42253, cited 7/11/2025) and Alexandria et al. for teaching MELD score, (D) in view of Rodriguez et al. (J Hepatol. 2014 May;60(5):955-61, previously cited 8/27/2024) for teaching ACLF grade, and NCT02770716 (Last updated posted 2019-08-14, referred as NCT02770716-2019, previously cited).
Claim 1 of the ‘777 application disclosed a formulation of terlipressin acetate with molecular formula C52H74N16O15S2•(C2H4O2)n and n is between 1.0 to 3.5 with a small portion of impurities.
Claim 1 of the ‘777 application did not disclosed administration the formulation of terlipressin acetate to treat hepatorenal syndrome.
The relevancy of Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, and (D) Rodriguez et al. for teaching ACLF grade and further in view of NCT02770716 as applied to claims 9-12, 16-17, 19-20, 24, 27-28, 30-45, and 47-48 not repeated here.
Because Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, and (D) Rodriguez et al. for teaching ACLF grade and further in view of NCT02770716 teach beneficial administration of terlipressin acetate to a pre-selected patient with clinical indicators of MELD score < 35, a serum creatinine level < 5 mg/dL, or an ACLF Grade< 3 likely to respond to terlipressin treatment, one of ordinary skill in the art would have found it obvious to beneficially combine the terlipressin acetate formulation taught by claim 1 of the ‘777 application and Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, (D) Rodriguez et al. for teaching ACLF grade and (E) NCT02770716 to treat a pre-selected patient group with hepatorenal syndrome.
Thus, claim 1 of the ‘777 application and Jamil et al. in view of (A) Lucassin, Wisniewski et al., and Alwadhi et al., in view of Bota et al. for teaching SpO2 level, (B) in view of Boyer et al. for teaching SCr level, (C) Ling et al. in view of Alexandria et al. for teaching MELD score, (D) Rodriguez et al. for teaching ACLF grade and (E) NCT02770716 are obvious to the instant claims 9-12, 16-17, 19-20, 24, 27-28, 30-45, and 47-48.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 1/9/2026 have been fully considered but they are not persuasive because the request of this rejection held in abeyance until all other rejections have been overcome does not overcome this provisional rejection.
Conclusion
No claim is allowed.
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/J.L/Examiner, Art Unit 1658
18-March-2026
/LI N KOMATSU/ Primary Examiner, Art Unit 1658