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
This application, filed on 21 August 2022, is a National Stage entry from International Application No. PCT/US2023/013526, filed on 21 February 2023, which claims benefit under 35 U.S.C. 120 to US Provisional Application No. 63/313,078.
Information Disclosure Statement
The information disclosure statements (IDSs) filed on 26 November 2024 and 26 March 2026 have been acknowledged and considered.
Claim Rejections - 35 USC § 112(b)
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 10-14 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.
Claims 10-11 and 13 recite the limitation: "The method of claim 1, wherein treating brain injury or intracranial hemorrhage…". The brain injury recited in claim 1 is “acute brain injury.” There is insufficient antecedent basis for this limitation in the claim and creates indefiniteness because the scope of “acute brain injury” in claim 1 is narrower in scope than “brain injury.” Claims 12 and 14 do not rectify the indefiniteness in the claims from which they depend (claim 11 and claim 13, respectively) and are therefore rejected.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 9 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 9 recites “The method of claim 1, wherein treating acute brain injury or intracranial hemorrhage…” The only brain injury listed in claim 1 is acute brain injury, which is narrower than the scope of the condition being treated in claim 9. The Specification defines “brain injury” which encompasses intracranial hemorrhage; however, the scope broadens claim 9 to methods of treatment of acute brain injury or intracranial hemorrhage. Dependent claim 9 must set forth and then specify a further limitation of the subject matter claimed from the referenced claim.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1, 8, 11-12, 15, 17-21, and 25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2011137511 (“Cruz”).
Claim 1 recites a method of treating acute brain injury in a patient in need thereof, comprising administering to a patient suffering from acute brain injury an effective amount of MW189. Claim 8 recites the administration of MW189 commences within from about between 4-6 hours, etc., after the patient suffers an acute brain injury. Claims 11-12 recite reduction of one or more pro-inflammatory cytokines like TNF-α, as a result of MW189 administration. Claim 15 recites administering MW189 in the range of 0.025mg/kg to 30 mg/kg. Claims 17-19 recite administering MW189 from one to four times per day, once or twice per day, and twice per day respectively. Claims 20-21 recite administering MW189 to the patient on at least two consecutive days and in the range of two to ten or more consecutive days, respectively.
Cruz teaches administration of 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-ylpiperazin-1-yl)- pyridazine (MW189) hydrochloride to an intracerebral hemorrhage (ICH) mouse model, which closely resembles ICH in humans. (p. 36, lines 14-21). The design of the study was disclosed: doses of MW189 were 1 mg/kg administered 30 minutes and 6-hours post-injury twice daily for a total of 5 days. The treatment of the ICH mice with MW189 reduced secondary damage to CNS tissue (pp. 37-38, Example 4). Accordingly, claims 1, 8, 15, and 17-21 are anticipated in view of Cruz.
Cruz also teaches administration of MW189 to mouse BV2 microglial cells pre-exposed to bacterial endotoxin lipopolysaccharide (LPS). Cruz teaches, in response to LPS the cells retain phenotypic features of microglia and produce proinflammatory cytokines and chemokines. The administration of MW189 led to dose-dependent inhibition of early cytokine marker TNF-α (p. 41, lines5-23, Figure 10). Accordingly, claims 11-12 are anticipated in view of Cruz.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-8, 11-21, and 25-30 are rejected under 35 U.S.C. 103 as being unpatentable over Cruz in view of Van Eldik et al., Clinical Pharmacology in Drug Development, 10: 131-143 (“Van Eldik”), further in view of Wilde et al., Journal of Neurotrauma. 2022;39(7-8):436-457; First Published January 1: (https://journals.sagepub.com/doi/10.1089/neu.2021.0099?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed) (“Wilde”).
Cruz teaches a method of treating a central nervous system injury in a subject comprising administering to a subject in need a composition comprising 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-ylpiperazin-1-yl) pyridazine hydrochloride (MW189) (claim 14). The term “central nervous system injury” includes any acute damage of an animal including traumatic brain injury, which includes intracranial hemorrhage, etc. (p. 18, lines 9-18; p. 19, lines 15-23). The term “subject” refers to mammals which includes humans (p. 22, lines 16-23). The doses of MW189 can be administered as one or more doses daily in a dose range of 0.01 mg/kg to 1 mg/kg (p. 27, lines 15-18). Example 4 teaches administration of MW189 at 1 mg/kg dose, 30 minutes and 6-hours post-injury twice daily for a total of 5 days, reduced secondary damage to CNS tissue. MW189 can be administered within 8 hours following a central nervous system injury from up to about 2 to 10 or 15 consecutive days post injury (p. 26, lines 32-33; p. 27, lines 1-3 and 11-26). Example 5 teaches administration of MW189 to mouse BV2 microglial cells pre-exposed to bacterial endotoxin lipopolysaccharide (LPS). In response to LPS, the cells retain phenotypic features of microglia and produce proinflammatory cytokines and chemokines. The administration of MW189 led to dose-dependent inhibition of early cytokine marker TNF-α (p. 41, lines 5-23, Figure 10). Cruz also teaches MW189 can be administered in combination with a second therapeutic agent, which includes a diuretic, an analgesic, a treatment for hypertension or hypertensive complications, a calcium channel blocker (e.g., nimodipine), etc. With respect to a second therapeutic agent, a method of treating central nervous system injury comprises administering MW189 and optionally at least one second therapeutic agent to ameliorate disease severity, disease symptoms, and/or periodicity of recurrence (pp. 10, lines 24-31; p. 28, lines 1-21).
Cruz does not teach detecting one or more biomarkers to diagnose or assess the severity of the acute brain injury, or assess response of the patient to MW189 nor does it teach a method comprising a monitoring a biomarker, like neurofilament light chain. While Cruz does teach monitoring of IL-10 (Example 5), it does not teach administration of MW-189 leads to increases in IL-10.
Van Eldik teaches first-in-human studies of MW189 administered to patients pre-exposed to a low dose endotoxin to induce a systemic inflammatory response. Treatment with MW189 led to lower levels of the proinflammatory cytokine TNFα and higher levels of the anti-inflammatory cytokine IL-10 (p. 131, Abstract). The pilot study was done to evaluate the pharmacodynamic effects of MW189 on endotoxin-induced changes in blood cytokine levels in healthy volunteers. The teachings state: “The results suggest engagement of pharmacological mechanism in humans, and provide support for further studies of MW189 for acute brain injury indications.” (p. 133, 1st column). Figure 4 shows significantly higher levels of the anti-inflammatory cytokine IL-10 and significantly lower levels of TNFα (p. 141, 2nd column).
Van Eldik does not teach detecting a biomarker to diagnose acute brain injury and assess the severity of acute brain injury prior to administration of MW189; followed by administration of MW189; then detection of one or biomarker to assess a change in severity of the acute brain injury as result of MW189 administration; and finally continuing, discontinuing, increasing, or decreasing administration of MW189. Furthermore, Van Eldik does not teach neurofilament light chain (NfL) as the biomarker being assessed.
Wilde teaches biomarker trajectories can monitor a patient’s status or specific pathophysiological processes over time and potentially even provide safety readouts of possible toxicity or side effects of an intervention in clinical traumatic brain injury (TBI) trials. Biomarker trajectories alone or as a panel of several different markers may be combined to serve as monitoring biomarkers tracking patient progression (p. 447, Figure 1, 1st column). Wilde states: “[Cerebrospinal fluid] CSF NfL levels show high sensitivity for acute neuronal injury, including in boxers with [mild] mTBI. NfL levels in serum correlate with their CSF levels (r = 0.71), and recent reports show elevation in acute TBI across the spectrum of severity…” and that “Combining GFAP, tau, and NfL showed satisfactory discriminatory power in relating to MRI-detected abnormalities, even in mTBI patients with a normal CT. This study highlights
the potential of a multi-modal approach to guide future clinical trials to improve medical decision making,
facilitate the use of MRI scanning, and stratify patients with brain injuries.” (pp. 443, 1st column; p. 449, 2nd column).
Cruz, Van Eldik, and Wilde are all analogous art to the claimed invention because they are in the same field of treating acute brain injury. Therefore, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA), before the effective filing date of the claimed invention, to combine the prior art elements to arrive at the method instantly claimed with a reasonable expectation of success MPEP §2143(G)). It would have been prima facie obvious; to administer MW189 twice daily to subjects, including humans, having acute brain injury, like intracranial hemorrhage, within 8 hours following the injury, for at least 2 consecutive days, as taught by Cruz; by diagnosing the injury using one or more biomarkers, like NfL, GFAP, etc., as taught by Wilde; and observe a decrease in pro-inflammatory cytokines, like TNFα, and an increase in anti-inflammatory markers, like IL-10, as taught by Van Eldik. Wilde provides motivation to a PHOSITA for using diagnostic biomarkers for TBI because it will be a critical enhancement for clinical trials; “…biomarker measures obtained prior to, during, and at the conclusion of an intervention can be used to assess treatment efficacy and classification accuracy (p. 438, Diagnostic Biomarkers). Accordingly, claims 1-8, 11-14, and 17-21 are prima facie obvious.
Regarding claims 15-16, Cruz teaches the doses of MW189 that can be administered as one or more doses daily in a dose range of 0.01 mg/kg to 1 mg/kg (vide supra). This range overlaps with the range instantly claimed is therefore prima facie obvious (MPEP §2144.05(I)).
Regarding claim 25, Cruz teaches that administration of MW189 to an ICH mouse model reduced secondary damage to CNS tissue (p. 38, lines 10-13).
Regarding claims 26-30, Cruz teaches MW189 can be administered in combination with a second therapeutic agent, which includes a diuretic, an analgesic, a treatment for hypertension or hypertensive complications, a calcium channel blocker (e.g., nimodipine), etc. With respect to a second therapeutic agent, a method of treating central nervous system injury comprises administering MW189 and optionally at least one second therapeutic agent to ameliorate disease severity, disease symptoms, and/or periodicity of recurrence (vide supra). Therefore, based on the teachings of Cruz it would be obvious to a PHOSITA to choose an anti-hypertensive and/or a calcium channel blocker, like nimodipine to administer in combination with MW189 because Cruz teaches a finite list of second therapeutic agents (MPEP §2143(E)).
Claims 9-10 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Cruz in view of Evaluation of CN-105 in Subject With Acute Supratentorial Intracerebral Hemorrhage (S-CATCH), Identifier:NCT03711903, 16 October 2018 (“NCT03711903”).
The teachings of Cruz are discussed above and are incorporated by reference herein.
Regarding claims 9-10 and 22-24, Cruz does not teach outcome measures of preventing or reducing the risk of mortality nor does it teach preventing brain infection, reducing the risk of hemorrhage expansion, or reducing perihematomal edema during and after treatment.
NCT03711903 teaches administration of CN-105 to patients with a confirmed diagnosis of intracerebral hemorrhage (Intervention, Eligibility Criteria, Condition). The outcomes measured are improvement in 30- and 90-day mortality (in hospital) and treatment related mortality. Other parameters measured were evaluation of hematoma expansion, CNS infection (e.g., cerebritis), and progression of perihematomal edema (Detailed Description).
Cruz and NCT03711903 are analogous art to the claimed invention because they are both in the same field of treating intracerebral hemorrhage. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective date of the claimed invention, to combine the prior art elements to yield reasonably predictable results. It would have been prima facie obvious to administer MW189 to treat subjects with acute brain injury, like intracerebral hemorrhage, as taught by Cruz, and measure the efficacy of the intervention through reduced risk or prevention of mortality, reduced risk of brain infection (e.g., cerebritis), reduced risk of hemorrhage expansion, and reduced perihematomal edema, as taught by NCT30711903. The inhibition of the progression or severity of symptoms of acute brain injury would be inherent upon the administration of MW189 to patients having the same. Notwithstanding the foregoing, it would have been prima facie obvious to a PHOSITA to incorporate the outcome measures taught in NCT30711903 because of the various pathologies that come with acute brain injury as taught by Cruz (p. 19, lines 15-20; p. 20, lines 16-26). Accordingly, claims 9-10 and 22-24 are prima facie obvious.
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 1-8, 11-21, and 25-30 are rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No.9,408,845 (“ ‘845 ”) in view of Cruz, Van Eldik, and Wilde. Although the claims at issue are not identical, they are not patentably distinct from each other because the teachings of the claims 1-10 of ’845 in view of Cruz, Van Eldik, and Wilde.
Claims 1-4 of ‘845 recite a method of treating a traumatic brain injury in a subject in need of treatment of a traumatic brain injury comprising administering 1.0 to 100 mg/kg, 1.0 to 50 mg/kg, and 1.0 to 20 mg/kg of body weight of MW189 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.
‘845 does not teach a method of treating brain injury in a patient comprising administering MW189 further comprising detecting biomarkers to test the severity of acute brain injury or assess response of the patient to MW189 or a combination thereof. ‘845 also does not teach specific biomarkers like NfL, TNFα, or IL-10, nor does it teach measuring outcomes like mortality or reduction in hemorrhage expansion or perihematomal edema.
Cruz teaches Cruz teaches a method of treating a central nervous system injury in a subject comprising administering to a subject in need a composition comprising 6-phenyl-4-pyridin-4-yl-3-(4-pyrimidin-2-ylpiperazin-1-yl) pyridazine hydrochloride (MW189) (claim 14). Example 4 teaches administration of MW189 at 1 mg/kg doses, 30 minutes and 6-hours post-injury twice daily for a total of 5 days reduces secondary damage to CNS tissue (p. 38, lines 10-13). MW189 can be administered within 8 hours following a central nervous system injury from up to about 2 to 10 or 15 consecutive days post injury (p. 27, lines 11-26). Example 5 teaches administration of MW189 to mouse BV2 microglial cells pre-exposed to bacterial endotoxin lipopolysaccharide (LPS). In response to LPS, the cells retain phenotypic features of microglia and produce proinflammatory cytokines and chemokines. The administration of MW189 led to dose-dependent inhibition of early cytokine marker THF-α (p. 41, lines 5-23, Figure 10). Cruz also teaches MW189 can be administered in combination with a second therapeutic agent, which includes a diuretic, an analgesic, a treatment for hypertension or hypertensive complications, a calcium channel blocker (e.g., nimodipine), etc. With respect to a second therapeutic agent, a method of treating central nervous system injury comprises administering MW189 and optionally at least one second therapeutic agent to ameliorate disease severity, disease symptoms, and/or periodicity of recurrence (pp. 10, lines 24-31; p. 28, lines 1-21).
Cruz does not teach detecting one or more biomarkers to diagnose or asses the severity of the acute brain injury, or assess response of the patient to MW189 nor does it teach a method comprising a monitoring a biomarker, like neurofilament light chain. While Cruz does teach monitoring of IL-10 (Example 5), it does not teach administration of MW-189 leads to increases in IL-10.
Van Eldik teaches first-in-human studies of MW189 administered to patients pre-exposed to a low dose endotoxin to induce a systemic inflammatory response. Treatment with MW189 led to lower levels of the proinflammatory cytokine THFα and higher levels of the anti-inflammatory cytokine IL-10 (p. 131, Abstract). The pilot study was done to evaluate the pharmacodynamic effects of MW189 on endotoxin-induced changes in blood cytokine levels in healthy volunteers. The teachings state: “The results suggest engagement of pharmacological mechanism in humans, and provide support for further studies of MW189 for acute brain injury indications.” (p. 133, 1st column). Figure 4 shows significantly higher levels of the anti-inflammatory cytokine IL-10 and significantly lower levels of TNFα (p. 141, 2nd column).
Van Eldik does not teach detecting a biomarker to diagnose acute brain injury and asses the severity of acute brain injury prior to administration of MW189, administration of MW189, detecting the one or biomarker to assess a change in severity of the acute brain injury, and continuing, discontinuing, increasing, or decreasing administration of MW189. Furthermore, Van Eldik does not teach neurofilament light chain (NfL) as the biomarker being assessed.
Wilde teaches biomarker trajectories can monitor a patient’s status or specific pathophysiological processes over time and potentially even provide safety readouts of possible toxicity or side effects of an intervention in clinical traumatic brain injury (TBI) trials. Biomarker trajectories alone or as a panel of several different markers may be combined to serve as monitoring biomarkers tracking patient progression (p. 447, Figure 1, 1st column). Wilde states: “[Cerebrospinal fluid] CSF NfL levels show high sensitivity for acute neuronal injury, including in boxers with [mild] mTBI. NfL levels in serum correlate with their CSF levels (r = 0.71), and recent reports show elevation in acute TBI across the spectrum of severity…” and that “Combining GFAP, tau, and NfL showed satisfactory discriminatory power in relating to MRI-detected abnormalities, even in mTBI patients with a normal CT. This study highlights
the potential of a multi-modal approach to guide future clinical trials to improve medical decision making,
facilitate the use of MRI scanning, and stratify patients with brain injuries.” (pp. 443, 1st column; p. 449, 2nd column).
‘845, Cruz, Van Eldik, and Wilde are all analogous art to the claimed invention because they are in the same field of treating acute brain injury. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective filing date of the claimed invention, to combine the prior art elements to arrive at the method instantly claimed with a reasonable expectation of success. It would have been prima facie obvious to administer MW189 to patients with traumatic brain injury, as taught by ‘845; twice daily to subjects, including humans, having acute brain injury, like intracranial hemorrhage, within 8 hours following the injury for at least 2 consecutive days, as taught by Cruz; by diagnosing the injury using one or more biomarkers, like NfL, GFAP, etc., as taught by Wilde; and observe a decrease in pro-inflammatory cytokines, like TNFα, and an increase in anti-inflammatory markers, like IL-10, as taught by Van Eldik. Wilde provides motivation to a PHOSITA for using diagnostic biomarkers for TBI because it will be a critical enhancement for clinical trials; “…biomarker measures obtained prior to, during, and at the conclusion of an intervention can be used to assess treatment efficacy and classification accuracy (p. 438, Diagnostic Biomarkers). Accordingly, claims 1-8, 11-14, and 17-21 are prima facie obvious.
obvious.
Regarding claims 15-16, ‘845 teaches the doses of MW189 that can be administered as 1.0 to 20 mg/kg of body weight (vide supra). This range overlaps with the range instantly claimed is therefore prima facie obvious (MPEP §2144.05(I)).
Regarding claim 25, Cruz teaches that administration of MW189 to an ICH mouse model reduced secondary damage to CNS tissue (p. 38, lines 10-13).
Regarding claims 26-30, Cruz teaches MW189 can be administered in combination with a second therapeutic agent, which includes a diuretic, an analgesic, a treatment for hypertension or hypertensive complications, a calcium channel blocker (e.g., nimodipine), etc. With respect to a second therapeutic agent, a method of treating central nervous system injury comprises administering MW189 and optionally at least one second therapeutic agent to ameliorate disease severity, disease symptoms, and/or periodicity of recurrence. Therefore, based on the teachings of Cruz it would be obvious to a PHOSITA to choose an anti-hypertensive and/or a calcium channel blocker, like nimodipine, to administer in combination with MW189 because Cruz teaches a finite list of second therapeutic agents (MPEP §2143(E)).
Claims 9-10 and 22-24 are rejected are rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-10 of ‘845 in view of Cruz and Evaluation of CN-105 in Subject With Acute Supratentorial Intracerebral Hemorrhage (S-CATCH), Identifier:NCT03711903, 16 October 2018 (“NCT03711903”).
The recitations of ‘845 and the teachings of Cruz are discussed above and are incorporated by reference herein.
Regarding claims 9-10 and 22-24, ‘845 and Cruz does not teach outcome measures of preventing or reducing the risk of mortality nor does it teach preventing brain infection, reducing the risk of hemorrhage expansion, or reducing perihematomal edema during and after treatment.
NCT03711903 teaches administration of CN-105 to patients with a confirmed diagnosis of intracerebral hemorrhage (Intervention, Eligibility Criteria, Condition). The outcomes measured are improvement in 30- and 90-day mortality (in hospital) and treatment related mortality. Other parameters measured were evaluation of hematoma expansion, CNS infection (e.g., cerebritis), and progression of perihematomal edema (Detailed Description).
‘845, Cruz, and NCT03711903 are analogous art to the claimed invention because they are both in the same field of treating brain injury like intracerebral hemorrhage. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective date of the claimed invention, to combine the prior art elements to yield reasonably predictable results. It would have been prima facie obvious to administer MW189 to treat subjects with brain injury, as taught by ‘845, like intracerebral hemorrhage, as taught by Cruz, and measure the efficacy of the intervention through reduced risk or prevention of mortality, reduced risk of brain infection (e.g., cerebritis), reduced risk of hemorrhage expansion, and reduced perihematomal edema, as taught by NCT30711903. The inhibition of the progression or severity of symptoms of acute brain injury would be inherent upon the administration of MW189 to patients having the same. Notwithstanding the foregoing, it would have been prima facie obvious to a PHOSITA to incorporate the outcome measures taught in NCT30711903 because of the various pathologies that come with acute brain injury as taught by Cruz (p. 19, lines 15-20; p. 20, lines 16-26). Accordingly, claims 9-10 and 22-24 are prima facie obvious.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHIL CHANDER AGGARWAL whose telephone number is (571)272-7755. The examiner can normally be reached 7am-5pm.
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/SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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