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 .
Priority
Acknowledgement is made of Applicants’ claim for benefit of U.S. Provisional Application 63/379,518 (filed 10/14/2022).
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 12/08/2025 in response to a Restriction requirement is acknowledged.
Claims 1, 5, 9-10, 14-15, and 19-24 read on the elected invention and are examined on the merits herein.
Claim Objections
Claims 10, 14, 19, and 21-22 are objected to because of the following informalities:
Regarding claim 10: Line 7 of claim 10 recites, “…is administered 5 min to 6 hr after after administering…”; this should read, “…is administered 5 min to 6 hr after
Regarding claims 14, 19: These instant claims recited the limitation “…is in a dosage form of solid, semi-solid, or liquid dosage form…”; the two separate recitations of dosage form is redundant.
Regarding claims 21, 22: These claims end in a comma instead of a period.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 5, 9-10, 14-15, and 19-24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1: A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation wherein the resuscitation fluid comprises whole blood, plasma/red blood cells/platelets, crystalloid solution; colloid solution comprising human albumin, hydroxyl ethyl starch (HES), or dextran; hypertonic saline (5 ml/kg NaCl 7.5%) with or without dextran; or oxygen-carrying blood substitutes, or a combination thereof, and the claim also recites wherein, the resuscitation fluid (i) is fresh whole blood or plasma/red blood cells/platelets, optionally at a ratio of about 1: about 1: about 1; or (ii) is a colloid solution comprising human albumin, and, optionally, wherein the resuscitation fluid further comprises fibrinogen which is the narrower statement of the limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claim.
Additionally, the formatting of claim 1 makes it difficult to understand, which is further compounded by the narrower limitation following recitation of the broad limitation. For instance, lines 10-11 of claim 1 recite, “…wherein the resuscitation fluid comprises whole blood, plasma/red blood cells/platelets, crystalloid solution…”, followed by the recitation of “…wherein the resuscitation fluid (i) is whole blood or plasma/red blood cells/platelets, optionally at a ratio…” in lines 19-20. Should the limitation recited in lines 10-11 read whole blood or plasma/red blood cells/platelets in a crystalloid solution? Is the comma preceding crystalloid solution meant to be a semicolon, thus separating the crystalloid solution from the whole blood and plasma/red blood cells/platelets in the Markush group of useable alternatives for the resuscitation fluid limitation? Whole blood necessarily comprises plasma/red blood cells/platelets, further adding to the lack of clarity. The formatting of claim 1 is problematic for the limitation recited in lines 21-22, as well; specifically, it is unclear if the limitation “…and, optionally, wherein the resuscitation fluid further comprises fibrinogen” is meant to apply to the colloid solution recited in (ii), or meant to apply generally to the resuscitation fluid of any of the alternatives as recited in lines 10-13 or lines 19-22.
In order to give the scope of claim 1 its broadest reasonable interpretation, whole blood, plasma/red blood cells/platelets, and crystalloid solution are interpreted as three separate alternatives for the resuscitation fluid (supported by par. 2 on pg. 4 of the instant specification), and the limitations recited in (i) and (ii) are not given any patentable weight.
Following the claim interpretation set forth above, it is recommended to reformat claim 1 in order to precisely define the metes and bounds of the invention; e.g., A method for reducing organ failure and/or improving survivability in a patient with severe hemorrhage or hemorrhagic shock, comprising steps of:
a) administering resuscitation fluid through intravenous route, wherein the resuscitation fluid comprises one or more of:
whole blood; plasma/red blood cells/platelets; crystalloid solution; colloid solution comprising human albumin, hydroxyl ethyl starch (HES), or dextran; hypertonic saline (5 ml/kg NaCl 7.5%) with or without dextran; oxygen-carrying blood substitutes; or a combination thereof;
optionally wherein the administering comprises administering an aliquot of 250 mL repeatedly up to 2000 mL while continuously monitoring a systolic blood pressure, radial pulse, and/or sensorium signs;
optionally wherein the resuscitation fluid further comprises fibrinogen;
b) administering at least one composition comprising a therapeutically effective amount of anti-hemorrhage agent one time or multiple times, wherein the anti-hemorrhage agent comprises one or more of:
prolyl hydroxylase domain inhibitor (PHDi); antifibrinolytic agent; bradykinin receptor antagonist; or a combination thereof that can be co-administered; and
c) optionally administering vasopressors and/or inotropic agents, wherein the vasopressor or inotropic is vasopressin, norepinephrine, epinephrine, dobutamine, or their synthetic equivalents.
Claims 5, 9-10, 14-15, and 19-24 depend from claim 1, inherit its deficiencies, and are likewise rejected for indefiniteness.
Regarding claims 5, 10, 23: The phrase ‘in particular’ renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For purposes of examination herein, under broadest reasonable interpretation, the phrase ‘in particular’ is interpreted akin to ‘optionally’.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 5, 9, 15, and 19-20 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Thiemermann, et al. (US 2015/0297558).
Thiemermann, et al. teaches the treatment of trauma hemorrhage or trauma hemorrhage-induced organ injury (Abstract).
Regarding claim 1: Thiemermann, et al. teaches a method of treating trauma hemorrhage trauma hemorrhage-induced injury, and trauma hemorrhage-induced multiple organ failure comprising administering a resuscitation solution intravenously (pars. 0119-0120), disclosing an embodiment wherein the resuscitation fluid comprises a colloid volume expander comprising albumin, dextran, blood, and etherified starch (par. 0102); further disclosed is an embodiment wherein the resuscitation fluid further comprises an antifibrinolytic agent (par. 0111). As evidenced by Thiemermann, et al., etherified starch is also known as hydroxyethyl starch (par. 0099); thus, the method of Thiemermann, et al. reads on the method for reducing organ failure and/or improving survivability in a patient with severe hemorrhage or hemorrhagic shock, comprising steps of administering resuscitation fluid through intravenous route, administering at least one composition comprising a therapeutically effective amount of anti-hemorrhage agent one time or multiple times, wherein the resuscitation fluid comprises whole blood; wherein the resuscitation fluid comprises colloid solution comprising human albumin, hydroxyl ethyl starch (HES), and dextran; and wherein the anti-hemorrhage agent comprises antifibrinolytic agent limitations recited in claim 1.
Regarding claim 5: Claim 5, when read as a whole, states: A method for reducing organ failure and/or improving survivability in a patient with severe hemorrhage or hemorrhagic shock, comprising steps of a. administering resuscitation fluid through intravenous route, and b. administering at least one composition comprising a therapeutically effective amount of anti-hemorrhage agent one time or multiple times, wherein the anti-hemorrhage agent comprises prolyl hydroxylase domain inhibitor (PHDi), antifibrinolytic agent, bradykinin receptor antagonist, or combination thereof that can be co-administered; wherein the PHDi is one selected from a group consisting of roxadustat (FG-4592), daprodustat (GSK-1278863), vadadustat (AKB-6548), molidustat (BAY 85-3934), enarodustat (JTZ-951), and MK-8617.
Thiemermann, et al. teaches a method wherein the anti-hemorrhage agent comprises an antifibrinolytic agent, and thus anticipates claim 5.
Regarding claim 9: Claim 9, when read as a whole, states: A method for reducing organ failure and/or improving survivability in a patient with severe hemorrhage or hemorrhagic shock, comprising steps of a. administering resuscitation fluid through intravenous route, and b. administering at least one composition comprising a therapeutically effective amount of anti-hemorrhage agent one time or multiple times, wherein the anti-hemorrhage agent comprises prolyl hydroxylase domain inhibitor (PHDi), antifibrinolytic agent, bradykinin receptor antagonist, or combination thereof that can be co-administered; wherein the PHDi is one selected from a group consisting of roxadustat (FG-4592), daprodustat (GSK-1278863), vadadustat (AKB-6548), molidustat (BAY 85-3934), enarodustat (JTZ-951), and MK-8617; and wherein the composition comprising PHDi is in a solid, semi-solid, or liquid dosage form, and administered orally or intravenously.
Thiemermann, et al. teaches a method wherein the anti-hemorrhage agent comprises an antifibrinolytic agent, and thus anticipates claim 9.
Regarding claim 15: Claim 15, when read as a whole, states: A method for reducing organ failure and/or improving survivability in a patient with severe hemorrhage or hemorrhagic shock, comprising steps of a. administering resuscitation fluid through intravenous route, and b. administering at least one composition comprising a therapeutically effective amount of anti-hemorrhage agent one time or multiple times, wherein the anti-hemorrhage agent comprises prolyl hydroxylase domain inhibitor (PHDi), antifibrinolytic agent, bradykinin receptor antagonist, or combination thereof that can be co-administered; wherein the bradykinin receptor antagonist is a bradykinin B2 receptor antagonist, icatibant.
Thiemermann, et al. teaches a method wherein the anti-hemorrhage agent comprises an antifibrinolytic agent, and thus anticipates claim 15.
Regarding claim 19: Claim 19, when read as a whole, states: A method for reducing organ failure and/or improving survivability in a patient with severe hemorrhage or hemorrhagic shock, comprising steps of a. administering resuscitation fluid through intravenous route, and b. administering at least one composition comprising a therapeutically effective amount of anti-hemorrhage agent one time or multiple times, wherein the anti-hemorrhage agent comprises prolyl hydroxylase domain inhibitor (PHDi), antifibrinolytic agent, bradykinin receptor antagonist, or combination thereof that can be co-administered; wherein the bradykinin receptor antagonist is a bradykinin B2 receptor antagonist, icatibant; and wherein the composition comprising bradykinin receptor antagonist is in a dosage form of solid, semi-solid, or liquid dosage form, and administered through oral, parenteral, or topical route.
Thiemermann, et al. teaches a method wherein the anti-hemorrhage agent comprises an antifibrinolytic agent, and thus anticipates claim 19.
Regarding claim 20: Thiemermann, et al. teaches an embodiment wherein the resuscitation fluid further comprises a pharmaceutically acceptable excipient (par. 0057); this anticipates the wherein the composition further comprises pharmaceutically suitable excipients limitation recited in claim 20.
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.
Claims 1, 5, 9, 15, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Thiemermann, et al. (US 2015/0297558) in view of White, et al. (J Trauma Acute Care Surg. 2017), Henry, et al. (Am J Hematol. 2021), and Jiang, et al. (Acta Pharmacol Sin. 2012); as evidenced by Caulier and Sankaran (Blood. 2022).
The teachings of Thiemermann, et al. are set forth above. Claims 1, 5, 9, 14-15, and 19-20 are anticipated by Thiemermann, et al.; this rejection will focus on the limitations of claims 5 and 9 which are not anticipated by the disclosure.
White, et al. teaches hemorrhagic blood failure (Title).
Henry, et al. teaches roxadustat for the treatment of anemia in an open-label, dose-selection, lead-in stage of a phase 3 study (Title).
Jiang, et al. teaches local inhibition of hypoxia-inducible factor-1α alleviates lung injury induced by trauma and hemorrhagic shock (Abstract).
Regarding claims 1, 5, 9: It is set forth above Thiemermann, et al. anticipates claim 1. Thiemermann, et al. does not teach the embodiment wherein the anti-hemorrhage agent comprises a prolyl hydroxylase domain inhibitor (PHDi).
However, White, et al. teaches trauma victims having both tissue injury and hemorrhagic shock are susceptible to intrinsic hemorrhagic blood failure (pg. S42; col. 1, par. 1); hemorrhagic blood failure is defined as an emergent state of blood that arises during accumulation of a critical level of oxygen debt, wherein critically low tissue oxygen delivery (i.e., hypoxia), endotheliopathy, platelet dysfunction, and coagulopathy are present (pg. S41; col. 2, par. 3). Once the lower threshold for critical oxygen delivery is surpassed, oxygen becomes maximally extracted from the blood by tissues, and anaerobic metabolism increases (pg. S42; col. 2, par. 2). The burden of accumulated oxygen debt must be repaid by increasing oxygen delivery above baseline levels to restore metabolic function; therefore, simply returning oxygen delivery to normal basal levels after accumulation of oxygen debt is insufficient to prevent subsequent organ injury (pg. S43; col. 1, par. 1).
Henry, et al. teaches hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) targets HIF-α for degradation through hydroxylation under normoxic conditions, but is unable to hydroxylate HIF-α during hypoxia; orally-administered roxadustat mimics the body's natural response to hypoxic conditions by inhibiting HIF-PH and therefore preventing hydroxylation of HIF-α, which allows for the transcription and expression of genes necessary for erythropoiesis (pg. 175; col. 1, par. 1). As evidenced by Caulier and Sankaran, ~200 billion red blood cells need to be produced every day via erythropoiesis to enable effective oxygen transport (Abstract).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Thiemermann, et al. by incorporating a step of administering roxadustat as taught by Henry, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so for the reasons disclosed by White, et al.; namely to increase oxygen delivery above baseline levels to restore metabolic function after accumulation of oxygen debt in order to attenuate subsequent organ injury (pg. S43; col. 1, par. 1). Further, one skilled in the art would have a reasonable expectation of success, as Jiang, et al. teaches administration of HIF-α inhibitor YC-1 in rats significantly ameliorated severe lung injury and intestinal injury in an in vivo model of trauma and hemorrhagic shock (pg. 637; col. 2, par. 2).
Thus, the modified method of Thiemermann, et al. as set forth above renders obvious the wherein the anti-hemorrhage agent comprises prolyl hydroxylase domain inhibitor (PHDi) limitation recited in claim 1, the wherein the PHDi is roxadustat limitation recited in claim 5, and the wherein the composition comprising PHDi is in a solid form and administered orally limitation recited in claim 9.
Claims 1, 5, 9-10, 14-15, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Thiemermann, et al. (US 2015/0297558) in view of Susin Pires, et al. (WO 2021/236227), as evidenced by the Federal Drug Administration (“Lysteda [tranexamic acid] Labeling Information.” 2009).
The teachings of Thiemermann, et al. are set forth above. Claims 1, 5, 9, 14-15, and 19-20 are anticipated by Thiemermann, et al.
Susin Pires, et al. teaches methods of treating plasma protein imbalances or depletion (Abstract).
Regarding claim 10: It is set forth above Thiemermann, et al. anticipates claim 1. Thiemermann, et al. does not explicitly teach the antifibrinolytic agent as selected from a group consisting of tranexamic acid, aminocaproic acid, and aprotinin, and in particular tranexamic acid, as required by the limitations recited in claim 10.
However, Susin Pires, et al. teaches antifibrinolytic administration to patients with severe bleeding within 3h of traumatic injury appears to decrease death from major bleeding, wherein tranexamic acid decreased overall mortality with given in the first 8h after injury (pg. 28, lines 20-32).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Thiemermann, et al. by using tranexamic acid as the antifibrinolytic agent, as taught by Susin Pires, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would be motivated to do so in order to decrease the mortality risk, as disclosed by Susin Pires, et al. Further, as Thiemermann, et al. teaches the use of an antifibrinolytic agent in the method, one skilled in the art would have more than a reasonable expectation of success.
Thus, the modified method of Thiemermann, et al. as set forth above renders obvious the wherein the antifibrinolytic agent is tranexamic acid limitation recited in claim 10.
Regarding claim 14: Following the above discussion, as evidenced by the FDA, tranexamic acid is available as tablets for oral administration (pg. 2, par. 2.1); this reads on the wherein the composition comprising antifibrinolytic agent is in a solid dosage form and administered through oral route limitation recited in claim 14.
Claims 1, 5, 9, 15, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Thiemermann, et al. (US 2015/0297558) in view of Wu, et al. (Blood. 2019), as evidenced by Abraham, et al. (Eur J Pharmacol. 2006).
The teachings of Thiemermann, et al. are set forth above. Claims 1, 5, 9, 15, and 19-20 are anticipated by Thiemermann, et al.; this rejection will focus on the limitations of claims 15 and 19 which are not anticipated by the disclosure.
Wu, et al. teaches the mitigation of vascular permeability using bradykinin receptor antagonist in rats with polytrauma and hemorrhagic shock (Title).
Regarding claims 1, 15, 19: It is set forth above Thiemermann, et al. anticipates claim 1. Thiemermann, et al. does not teach the embodiment wherein the anti-hemorrhage agent comprises a bradykinin receptor antagonist.
However, Wu, et al. teaches rats under anesthesia with isoflurane received polytrauma followed by hemorrhage before receiving normal saline, bradykinin receptor-2 antagonist (BR-2A) (HOE140 0.5 mg/kg), tranexamic acid (TXA) (20 mg/kg), or combination of HOE140/TXA via femoral vein (pg. 1; "Method"); BR-2A and TXA independently mitigate tissue-specific vascular permeability in trauma and hemorrhagic shock (pg. 2; "Conclusions"). As evidenced by Abraham, et al., HOE140 is also known as icatibant (pg. 217; Table 1).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Thiemermann, et al. by incorporating a step of administering icatibant, as taught by Wu, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would have been motivated to do so for the mitigation of tissue-specific vascular permeability provided by icatibant in hemorrhage, as disclosed by Wu, et al. Further, as the same disclosure teaches this mitigation in vivo, one would have a reasonable expectation of success.
Thus, the modified method of Thiemermann, et al. as set forth above renders obvious the wherein the anti-hemorrhage agent comprises bradykinin receptor antagonist limitation recited in claim 1, the wherein the bradykinin receptor antagonist is a bradykinin B2 receptor antagonist, icatibant limitation recited in claim 15, and the wherein the composition comprising bradykinin receptor antagonist is in a dosage form of liquid dosage form, and administered through parenteral route limitation recited in claim 19.
Claims 1, 5, 9, 15, and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Thiemermann, et al. (US 2015/0297558) in view of Cannon (N Engl J Med. 2018).
The teachings of Thiemermann, et al. are set forth above. Claims 1, 5, 9, 14-15, and 19-20 are anticipated by Thiemermann, et al.
Cannon teaches the pathobiology of hemorrhagic shock and treatment approaches for patients (Abstract).
Regarding claim 21: It is set forth above Thiemermann, et al. anticipates claim 1. Thiemermann, et al. does not teach the limitation recited in the instant claim.
However, Cannon teaches in patients with severe hemorrhage or hemorrhagic shock, the chain of survival starts with primary prevention and prehospital intervention, including hemorrhagic identification and control, e.g., direct pressure, tourniquet, hemostatic dressing; hospital-level care should include rapid control of all sites of hemorrhage, e.g., surgical exploration, angiography with embolization (pg. 374; Fig. 2). This reads on the wherein the method further comprises physically controlling the hemorrhage limitation recited in claim 21.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Thiemermann, et al. by controlling the site of the bleeding as taught by Cannon. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would have been motivated to do so because Cannon teaches prompt action to stop the bleeding is lifesaving, and rapidly controlling the source of hemorrhage limits the depth and duration of the shock state (pg. 373; col. 1, par. 2). While success in the sense of patient survival is never certain in trauma medicine, one skilled in the art would have a reasonable expectation of success that physically controlling the hemorrhage would offer a greater chance of survival to the patient.
This renders obvious the limitations recited in claim 21.
Claims 1, 5, 9, 15, 19-20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Thiemermann, et al. (US 2015/0297558) in view of Moore, et al. (J Trauma Acute Care Surg. 2020).
The teachings of Thiemermann, et al. are set forth above. Claims 1, 5, 9, 14-15, and 19-20 are anticipated by Thiemermann, et al.
Moore, et al. teaches calcium supplementation in adults with traumatic hemorrhagic shock (Abstract).
Regarding claim 22: It is set forth above Thiemermann, et al. anticipates claim 1. Thiemermann, et al. does not teach the limitation recited in the instant claim.
However, Moore, et al. teaches a significant risk of hypocalcemia in patients after administration of blood products due to the presence of citrate (pg. 593; col. 1, par. 3), disclosing hypocalcemia is independently associated with decreased survival in patients having undergone hemorrhagic shock (pg. 593; col. 1, par. 2). Moore, et al. also teaches 10% calcium gluconate is recommended as a preferred calcium supplement over 10% calcium chloride due to the low iatrogenic effects of the former (pg. 594; col. 1, par. 3).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Thiemermann, et al. by co-administering 10% calcium gluconate as taught by Moore, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would be motivated to do so to decrease the risk of mortality, as taught by Moore, et al. Additionally, one skilled in the art would have a reasonable expectation of success, as Moore, et al. teaches calcium supplementation is recommended by the published European guidelines for management of major bleeding after trauma (pg. 594; col. 1, par. 3).
Thus, the modified method of Thiemermann, et al. set forth above renders obvious the wherein the anti-hemorrhage agent or combination thereof are co-administered with calcium supplement, wherein the calcium supplement is calcium gluconate limitation recited in claim 22.
Claims 1, 5, 9-10, 14-15, and 19-24 are rejected under 35 U.S.C. 103 as being unpatentable over Thiemermann, et al. (US 2015/0297558) in view of Cannon (N Engl J Med. 2018), further in view of Moore, et al. (J Trauma Acute Care Surg. 2020), and as evidenced by the Federal Drug Administration (“Calcium Gluconate Labeling Information.” 2017).
The teachings of Thiemermann, et al., Cannon, and Moore, et al. are set forth above. Claims 1, 5, 9, 14-15, and 19-20 are anticipated by Thiemermann, et al.
Regarding claims 23-24: It is set forth above Thiemermann, et al. in view of Cannon renders obvious claim 21, and Thiemermann, et al. in view of Moore, et al. renders obvious claim 22. For the same reasons set forth in those rejections, it would have been prima facie obvious to a person having ordinary skill in the art to have further modified the method of Thiemermann, et al. by incorporating both physical control of the hemorrhage as well as administration of 10% calcium gluconate. This modified method does not explicitly read on the limitations recited in the instant claims.
However, as evidenced by the FDA, calcium gluconate contains 100 mg/mL (pg. 1; “Dosage forms and strengths”), and the recommended dosage for adults for continuous infusion equates to 0.054-0.215 mL/kg (pg. 3; Table 1); this renders obvious the wherein the calcium supplement is 10% calcium gluconate or calcium chloride and administered at a dose of 0.01-1 mL/kg, in particular 0.1 mL/kg limitation recited in claim 23, and the wherein the calcium supplement is in a liquid dosage form for parenteral administration limitation recited in claim 24.
It would have been prima facie obvious to a person having ordinary skill in the art to have further modified the method of Thiemermann, et al. by using the FDA guidelines for recommended dosage for continuous infusion. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so because the FDA is the regulatory authority for pharmaceutical drugs in the United States; additionally, this regulatory authority grants a reasonable expectation of success to a person skilled in the art following guidelines thereof.
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 1, 5, and 9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-5 of copending Application No. 18/805,212 in view of Holcomb, et al. (JAMA. 2015).
Holcomb, et al. teaches transfusion of plasma, platelets, and red blood cells in hemorrhagic shock (Abstract).
Regarding claims, 1, 5, 9: Copending claims 1-2 teaches a method of treating hemorrhagic shock in a subject in need, the method comprising administering a therapeutically effective amount of a composition comprising at least one PHDi; copending claim 4 teaches the PHDi as MK-8617; copending claim 5 teaches the administering comprises oral or intravenous administration. These copending claims read on the method for reducing organ failure and/or improving survivability in a patient with severe hemorrhage or hemorrhagic shock, comprising administering at least one composition comprising a therapeutically effective amount of anti-hemorrhage agent one time or multiple times, wherein the anti-hemorrhage agent comprises prolyl hydroxylase domain inhibitor (PHDi) limitation recited in instant claim 1, the wherein the PHDi is MK-8617 limitation recited in instant claim 5, and the wherein the composition comprising PHDi is in a solid for liquid dosage form, and administered orally or intravenously limitation recited in instant claim 9.
The copending claims do not teach the administration of resuscitation fluid, as required by the remaining limitation recited in instant claim 1.
However, Holcomb, et al. teaches rapid hemorrhage control comprising intravenous transfusion of a blood product at a ratio of 1:1:1 for plasma to platelets to red blood cells (pg. 472; pars. 2, 6); this reads on the administering resuscitation fluid through intravenous route, wherein the resuscitation fluid comprises plasma/red blood cells/platelets at a ratio of about 1: about 1: about 1 limitation recited in claim 1.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of copending Application No. 18/805,212 by incorporating a step of transfusion of blood product at a ratio of 1:1:1 for plasma to platelets to red blood cells, as taught by Holcomb, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do because, as taught by Holcomb, et al., severely injured patients experiencing hemorrhagic shock often require massive transfusion, and earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), is associated with improved outcomes; likewise, one skilled in the art would have a reasonable expectation of success because of the improved outcomes disclosed by Holcomb, et al. (Abstract). This renders obvious the limitations recited in instant claim 1, 5, and 9.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633