DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment, filed 06/29/2026, has been entered.
Claims 1-31 have been canceled.
Claims 32-61 are pending and currently under examination as they read on a method treating a patient with type-1 hepatorenal syndrome (HRS-1) comprising administering terlipressin acetate.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 32-45, 49-50 are rejected under 35 U.S.C. 102(a)(1) are rejected as being anticipated by Wong et al. (NEJM March 2021; 384:818-828; including the Protocol and Supplemental Appendix made available with the full text of the Wong article at NEJM.org; reference of record).
Addition of claims 32-43 to this rejection was necessitated by Applicant’s amendment, specifically in the deletion of the limitation of “oxygenation level (SpO2) >90%”, filed 06/29/2026.
Wong et al. taught a method for treating a patient having: 1) HRS-1, (see Wong et al. Abstract); 2) MELD score < 35, (see Wong et al. Table 1; Supplemental Appendix Figure S7); 3) Serum creatinine (Scr) level < 5 mg/dL (see Table 1 Wong et al.) and 4) ACLF grade < 3; (see Supplemental Appendix Table S8g) comprising the method steps of: 1)obtaining these above baseline levels; 2) intravenously administering a pharmaceutical composition comprising terlipressin (see Protocol page 6 of 90); 3) wherein the patient does not have history of severe cardiovascular conditions (see Protocol page 8 of 108, Section 8, #13; Wong et al. page 820, first paragraph); and 4) wherein the mean arterial pressure increased after the treatment (Supplemental Appendix Figures S9a and S9b). Wong et al. also taught administering 100 g per day of albumin (Protocol page 47 of 109), measuring the baseline serum creatinine level, (see Supplemental Appendix Fig S10); obtaining a Scr level during the initial 1-4 days of administration (Protocol Table 13-1; Supplemental Appendix Table S8); continuing administration of the pharmaceutical composition until at least two Scr values less than or equal to 1.5 mg/dL (page 819, right column, second paragraph) and obtaining a baseline oxygen saturation prior to administration (Protocol page 64 of 108; Vital signs); monitoring fluid overload and discontinuing treatment when patient experiences fluid overload (Protocol page 34 of 90, 10.3.2.1.1 Management of Fluid Overload).
With regards to AUC24h, Cave and Cmax, it is noted that these are intrinsic properties of the terlipressin used in the study. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01.
Furthermore, with regards to increase in diastolic, systolic and mean arterial pressure and decrease in heart rate, it is noted that by performing the same method step of administering terlipressin, it would achieve these results. Where the prior art teaches performing the same method using the same drug or agent under the same conditions, the naturally resulting properties or effects of that treatment are inherent, even if the prior art did not recognize or expressly disclose those results. MPEP § 2112.02; In re May, 574 F.2d 1082 (CCPA 1978).
Moreover, given that the prior art taught the same method steps, it would necessarily yield patient with the above conditions having reduced adverse event up to 30 days, reduced mortality rate up to day 60 or improved 90-day survival compared to patients not meeting the conditions or the placebo group.
Response to Applicant’s argument
Applicant first argues that Wong does not anticipate the claimed treatment methods because Wong does not teach selecting/only treating patients having baseline MELD <35, SCr <5 mg/dL, and ACLF grade <3 and that Wong treated patients outside each claimed threshold—including MELD ≥35, SCr ≥5 mg/dL, and ACLF grade 3.
Applicant argues that Wong does not teach “only treating” patients having a MELD score < 35, serum creatinine level < 5 mg/dL, and ACLF grade < 3 because Wong did not exclude patients falling outside these thresholds. However, the claims do not require excluding patients having values outside the recited ranges. Rather, the claims require administration to a patient having the recited baseline characteristics. Wong expressly demonstrates administration of terlipressin to patients falling within each of the claimed ranges. In particular, Wong reports a baseline MELD score of approximately 33 in the terlipressin population (Figure S7), a baseline serum creatinine level of 3.5±1.0 mg/dL in the terlipressin group (Table 1), and baseline ACLF grades having a mean of 1.8, median of 2.0, and range of 1–3 in the terlipressin group (Supplemental Appendix, Table S8g). The fact that Wong additionally treated patients falling outside one or more of the claimed thresholds does not negate Wong’s disclosure of treating patients falling within the claimed ranges.
Applicant’s second argument of nonobviousness is not applicable to the anticipatory rejection.
Therefore, Applicant’s argument has not been found convincing.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 46-48, 51-61 are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (NEJM March 2021; 384:818-828; including the Protocol and Supplementary Appendix made available with the full text of the Wong article at NEJM.org) in view of Jubran (Critical Care 2015; 19:272).
The teaching of Wong et al. has been discussed above (see 102).
The only claim limitation Wong did not teach was that the HRS-1 patient having a baseline SpO2 greater than 90%. However, it would have been obvious for one of ordinary skill in the art to exclude patient with SpO2 baseline less than 90% or perform said monitoring throughout the course of treatment because Wong disclosed that terlipressin treatment was associated with respiratory failure (see, e.g., last paragraph on page 818). Upon reading the prior art teachings by, one of ordinary skill in the art would have been motivated to 1) take SpO2 reading before administering terlipressin; 2) not give terlipressin to patients whose SpO2 is less than 90% which is indicative of hypoxemia associated with respiratory failure and frequently in order to avoid hypoxia or respiratory symptoms. It is noted that oxygen saturation less than 90% is an art known marker for hypoxemia (see, e.g., Jubran on page 5, Clinical Applications). Therefore, one of ordinary skill in the art would have picked 90% as a threshold for detecting terlipressin-induced respiratory failure.
Therefore, the invention, as a whole, was prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Applicant’s argument
Applicant’s arguments have been fully considered but are not persuasive.
Applicant argues that Wong in view of Jubran would not have rendered the claimed invention obvious because Wong allegedly discourages treatment with terlipressin due to the increased incidence of serious adverse events, including respiratory failure and mortality, and because the prior art did not identify the presently claimed patient subpopulation as one in which terlipressin could be administered with an improved safety profile. Applicant further argues that the rejection improperly assumes that a person of ordinary skill in the art would have varied numerous patient-selection parameters until arriving at the claimed invention and that there would have been no reasonable expectation of success. Applicant also relies on alleged unexpected results and long-felt unmet need as evidence of nonobviousness. These arguments are not persuasive.
As explained above, the rejection does not rely upon a person of ordinary skill indiscriminately varying MELD score, serum creatinine, ACLF grade, and other patient characteristics until arriving at a successful combination. Rather, Wong already administered terlipressin to HRS-1 patients having the recited baseline characteristics, including a MELD score <35, serum creatinine level <5 mg/dL, and ACLF grade <3. The fact that Wong’s study also included patients having values outside the recited thresholds does not negate Wong’s teaching of administering terlipressin to patients meeting the claimed characteristics. The claims do not require that all patients outside the recited ranges be excluded from treatment.
The limitation not expressly taught by Wong is the requirement concerning a baseline SpO₂ greater than 90%. However, Wong expressly reported respiratory failure as an adverse event associated with terlipressin treatment. Thus, Wong itself provided a reason for a person of ordinary skill to assess a patient’s respiratory status before and during administration of terlipressin and to avoid administering the drug to patients already exhibiting impaired oxygenation. Jubran further teaches that an SpO₂ below 90% is a recognized clinical indicator of hypoxemia. Accordingly, a person of ordinary skill, seeking to retain the demonstrated HRS-1 reversal efficacy of terlipressin while reducing the risk of respiratory complications identified by Wong, would have had reason to select and treat patients having a baseline SpO₂ greater than 90%, with a reasonable expectation that patients without preexisting hypoxemia would be more suitable candidates for treatment. The proposed modification therefore represents the predictable application of a known clinical safety criterion to a known treatment-associated respiratory risk, rather than impermissible hindsight reconstruction.
Applicant’s reliance on In re Kubin and In re O’Farrell is therefore misplaced. The rejection does not assume that a skilled artisan would have varied “all parameters” or tried each of numerous possible patient populations without guidance from the prior art. Wong already provides the claimed treatment and patients having the recited MELD, serum creatinine, and ACLF characteristics, and specifically identifies respiratory failure as a safety concern. Jubran provides the art-recognized SpO₂ threshold relevant to that particular concern. Thus, the prior art provides both a reason to consider oxygen saturation and guidance as to the clinically relevant threshold.
Applicant’s assertion that Wong teaches away from the claimed invention is likewise unpersuasive. Although Wong reports increased respiratory adverse events associated with terlipressin, Wong also demonstrates that terlipressin is more effective than placebo in reversing HRS-1. A reference does not teach away merely because it identifies disadvantages or risks associated with an otherwise useful treatment. Rather, Wong’s disclosure of respiratory failure would have provided a reason to mitigate that known risk by identifying patients with adequate baseline oxygenation. Nothing identified by Applicant indicates that Wong criticizes, discredits, or otherwise discourages screening patients for hypoxemia before administering terlipressin. To the contrary, the respiratory safety concern identified by Wong provides the reason for the modification proposed in the rejection.
Applicant’s arguments regarding alleged unexpected results have also been considered but do not overcome the prima facie case of obviousness. Applicant attributes the alleged improvement in adverse events, respiratory-failure-related adverse events, mortality, and efficacy principally to a “mitigated population” having a baseline MELD score <35, serum creatinine <5 mg/dL, and ACLF grade <3. However, Wong already administered terlipressin to HRS-1 patients meeting those baseline characteristics. The later recognition that patients having particular baseline characteristics may exhibit favorable outcomes does not establish that administration of terlipressin to such patients was absent from the prior art.
Moreover, to the extent Applicant relies upon the alleged results as objective evidence of nonobviousness of the subject matter rejected over Wong and Jubran, the evidence has not been shown to establish that the alleged improvement is attributable to the feature relied upon to distinguish the claims from Wong—i.e., the requirement for a baseline SpO₂ greater than 90%. Applicant’s discussion and cited data principally compare populations defined by MELD score, serum creatinine, and ACLF grade. Applicant has not established that selecting patients having a baseline SpO₂ greater than 90%, as opposed to the other baseline characteristics already present in Wong, produced a result that would have been unexpected to one of ordinary skill. Accordingly, the evidence does not sufficiently rebut the rationale underlying the combination of Wong and Jubran.
Applicant’s argument concerning long-felt need is also acknowledged but is not sufficient to outweigh the evidence of obviousness. The evidence cited by Applicant establishes that there was a recognized need for safe and effective treatment of HRS-1 and that available treatment alternatives had limitations. However, the existence of a general need for improved HRS-1 therapy does not, by itself, demonstrate the nonobviousness of the presently claimed subject matter. In particular, Applicant has not sufficiently established that the alleged satisfaction of the long-felt need resulted from the distinguishing SpO₂ >90% limitation rather than from patient characteristics and treatment already present in Wong. Likewise, subsequent FDA actions and recognition of a more narrowly defined patient population have been considered, but such evidence does not negate the teachings available to the ordinarily skilled artisan before the effective filing date or establish that the presently claimed distinction would have been nonobvious.
Accordingly, when all evidence is considered as a whole, including Applicant’s evidence of alleged unexpected results and long-felt unmet need, the evidence of secondary considerations does not outweigh the strong evidence of obviousness. Wong teaches administration of terlipressin to HRS-1 patients having the recited MELD, serum creatinine, and ACLF characteristics and identifies respiratory failure as an important treatment-associated risk. Jubran establishes that an SpO₂ below 90% is a recognized indicator of hypoxemia. One of ordinary skill therefore would have been motivated to select patients having baseline SpO₂ greater than 90% for terlipressin treatment in order to avoid administering the drug to patients already exhibiting hypoxemia and thereby reduce the recognized risk of respiratory complications, with a reasonable expectation of success.
The rejection under 35 U.S.C. §103 over Wong in view of Jubran is therefore maintained.
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 32-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 10,335,452 in view Wong et al. (NEJM March 2021; 384:818-828; including the Protocol and Supplementary Appendix made available with the full text of the Wong article at NEJM.org) in view of Jubran (Critical Care 2015; 19:272).
The claims of patent ‘452 disclosed a method of treating HRS comprising administering terlipressin and assessing Scr. Although the patent claims did not disclose obtaining SpO2, assessing an ACLF grade or monitoring SpO2 level, it would have been obvious to perform these steps in view of Wong et al. and Jubran et al. as evidenced by the instant specification as discussed above (see 102 and 103). Therefore, the patent claims render obvious of the present claims in view of Wong and Jubran.
Applicant’s argument and Examiner’s Response are essentially same as above.
Claims 32-61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the following in view of Wong et al. (NEJM March 2021; 384:818-828; including the Protocol and Supplemental Appendix made available with the full text of the Wong article at NEJM.org) in view of Jubran (Critical Care 2015; 19:272).
Co-pending application
Claims
USSN 17104864
claims 16, 18, 19, 27, 31-43
USSN 17340765
claims 1-48
USSN 17976502
Claims 1-27
USSN 17976603
Claims 1, 3, 5, 7-24
USSN 17976606
Claims 9-12, 16, 17, 19, 20, 24, 27, 28, 30-32
USSN 19213363
Claims 1-21
USSN 18783546
Claims 1-4
USSN 17587442
claims 1-19
USSN 18431587
Claims 17-46
USSN 18783572
Claims 13-42
The copending claims disclosed methods of treating comprising administering terlipressin in adults with HRS and obtaining SpO2, assessing an ACLF grade, monitoring SpO2 level and/or assessing SCr. Therefore, the reference copending claims would render obvious of the present claims in view of Wong et al., and Jubran et al. (see 102 and 103).
This is a provisional nonstatutory double patenting rejection.
Applicant’s argument and Examiner’s Response are essentially same as above.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHARON X WEN whose telephone number is (571)270-3064. The examiner can normally be reached Mon-Fri 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SHARON X WEN/Primary Examiner, Art Unit 1641
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