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 .
Status
Claims 1, 3, 8, 9, 21-23, and 26 are pending and presented for examination.
Election/Restrictions
Applicant elected without traverse
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in the reply filed on 4/3/2024.
Priority
This application claims priority from application Serial No. 63/109,213, filed on 11/3/2020.
Information Disclosure Statement
The Information Disclosure Statement filed 6/20/2025 has been considered by the Examiner. The submission is in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Claim Objections
Claim 3 is objected to because of the following informalities:
The term “is present dissolved or dispersed in a pharmaceutically acceptable diluent as a pharmaceutical composition when administered” should be “is administered in the form of a pharmaceutical composition, wherein said compound or pharmaceutically acceptable salt thereof is dissolved or dispersed in a pharmaceutically acceptable diluent”. Appropriate correction is required.
Withdrawn Claim Rejections/Objections
Claims 1, 3, 8, 9, and 21-23 were rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. in view of Barbier et al., and Han. Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the obviousness rejection under 35 U.S.C. § 103 made of record in the previous Office Action, specifically, the addition of the limitation to claim 1 that requires the specific hyperinflammatory syndromes including sepsis and cytokine shock. Therefore, the rejection is hereby withdrawn.
Claim Rejections - 35 USC § 103
Rejection maintained, modified to address amendment
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.
Maintained - Claims 1, 3, 8, 9, 21-23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (“Naloxone Protects Rat Dopaminergic Neurons against Inflammatory Damage through Inhibition of Microglia Activation and Superoxide Generation.” The Journal of Pharmacology and Experimental Therapeutics (JPET 2000); Vol. 293, No. 2: 607-617) in view of Barbier et al. (US PG-PUB 2011/0105481), Han et al. (Folia Neuropathol. 2020; 58 (1): 57-69 DOI: https://doi.org/10.5114/fn.2020.94007) and Qin et al. (Glia. 2007 Apr 1; 55(5):453-62. doi:10.1002/glia.20467. PMID: 17203472; PMCID: PMC2871685).
Claimed invention
The claims are drawn to inhibiting an immune response mediated by one or more of TLR2, RAGE, CCR5, CXR4 and CD4 cell surface receptors in a subject having a hyperinflammatory syndrome (e.g., sepsis), the method comprising administering to the subject an effective amount of a compound such as
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in the absence of a mu opioid receptor (MOR)-binding effective amount of a separate MOR agonist or antagonist.
Prior art
Liu teaches that naloxone protects dopaminergic neurons against inflammatory damage in Parkinson’s disease (PD) by inhibiting microglia activation and superoxide generation, demonstrating the therapeutic benefit of suppressing microglial inflammatory responses. See title; abstract.
Liu does not teach:
1) a compound of formula A such as
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2) the immune response is mediated by one or more of TLR2, RAGE, CCR5, CXCR4 and CD4, or
3) a hyperinflammatory syndrome such as sepsis or cytokine storm.
Regarding 1) a compound such as C0105M: It was already known that compounds of Formula A
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such as
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were used to inhibit inflammation and pain in subjects. Barbier teaches a method of reducing one or both of inflammation and pain in a host mammal by administering a composition containing a compound of Formula A
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such as
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(or a pharmaceutically acceptable salt thereof). See Barbier, Claim 21 and Claim 46. The compound binds to filamin A – FLNA; the high-affinity binding site of naloxone (NLX) and naltrexone (NTX) – to reduce cell motility and inflammation and prevent the Gi/o-to-Gs coupling switch of mu opioid receptor (MOR) and is similar to or more active than DAMGO in activating MOR. See Barbier, 0023; see also 0004-0005. The glial inflammatory response has been implicated in neuropathic pain as well as the inflammatory neurotoxicity of neurodegenerative disease. Barbier further teaches that femtomolar amounts of naloxone and its inactive isomer, both known to bind FLNA, have been shown to reduce the microglial inflammatory response; i.e., pro-inflammatory factors and reactive oxygen species, of lipopolysaccharide-activated microglial cells (citing Liu et al.). See Barbier, 0004. FLNA controls cell motility by controlling the cycle of actin polymerization and depolymerization, allowing cells to move and to migrate. As actin depolymerization is linked to the inflammatory response, binding to FLNA suppresses inflammation by slowing actin polymerization and cell motility. See Barbier, 0004.
One of ordinary skill in the art (POSA) would have found it obvious to replace naloxone with a compound of Formula A such as
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to treat a subject with an inflammatory condition such as Parkinson's disease (PD) because Liu teaches naloxone can protect PD subjects by inhibiting microglial cell activity and associated inflammation and Barbier teaches that naloxone works by binding to FLNA and inhibiting microglial inflammatory response and further teaches that compounds of Formula A act similar to naloxone by binding to FLNA and inhibiting cell motility and inflammatory activity. The POSA would have sought to take advantage of the similar FLNA-binding activity shared between compounds of Formula A such as
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and naloxone in order to reduce inflammatory response by microglial cells in PD subjects because Liu teaches that naloxone treats PD by binding to FLNA and inhibiting microglial inflammatory response while Barbier also teaches that naloxone inhibits microglial response by binding FLNA and further teaches that compounds of Formula A such as
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works to inhibit inflammation in a similar fashion, i.e., binding FLNA.
Regarding 2) the immune response is mediated by one or more of TLR2, RAGE, CCR5, CXCR4 and CD4: It was already known that microglial cells are immune cells with TLR2 and RAGE receptors. Han teaches microglia are the immune effector cells of the central nervous system (CNS) after being activated. Microglia are involved in brain diseases such as brain injury, inflammation, multiple sclerosis, Alzheimer’s disease and recurrent seizures. Appropriate inhibition of microglial cell activation at the early stage can reduce the pathological damages caused by its activation. See 1st par., p. 57. Microglial cells express RAGE and TLR2 and have an increased expression of RAGE and TLR2 when activated. See p. 62-64; see also Figs. A and B.
One of ordinary skill in the art (POSA) would have found it obvious to inhibit activated microglial cells in order to reduce inflammatory damage induced by the activated microglial cells in PD subjects with a compound of formula A. Given that microglial cells are activated through TLR2 and/or RAGE, the POSA would have found it obvious to inhibit the microglial activation including activation mediated by TLR2 and/or RAGE. The POSA would have sought to reduce activation with a compound of Formula A as suggested above including activation mediated by TLR2 and/or RAGE since these are involved in increasing microglial cell activity and said increased activity is pathologically linked to Parkinson’s disease. Furthermore, the artisan would have had a reasonable expectation of success that the administration of the compound to the subject would consequently lead to the administration to the microglial immune cell.
Regarding 3) the hyperinflammatory syndrome, e.g., sepsis or cytokine storm:
Sepsis was known to occur in PD patients and lead to progressive dopaminergic (DA) neurodegeneration, which exacerbates PD. For example, studies by Qin conducted with lipopolysaccharide (LPS, strain O111:B4 (E. coli strain) – see p. 3 ‘Reagents’) to induce an overactive inflammatory cytokine release, including peripheral TNFα, indicate that a single occurrence of sepsis and peripheral inflammation may result in self-propelling neuroinflammation and progressive DA neurodegeneration. See p. 2, last par.; see also three paragraphs under section ‘Peripheral Inflammation Causes Chronic Neuroinflammation Through TNFα’ spanning pp. 6 and 7; see also p. 5, last par. Qin teaches that LPS demonstrated that peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated proinflammatory factors; and (2) induce delayed and progressive loss of DA neurons in the SN. Qin’s findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease as systemic LPS causes neuroinflammation and progressive neurodegeneration. See title; abstract.
The POSA would have found it obvious to treat a PD patient with sepsis and overactive self-propelling neuroinflammatory response due to increased release of cytokines (e.g., TNFα), i.e., cytokine storm, with the claimed compound because Liu, Barbier and Han suggest treating PD by binding FLNA to decreasing microglia activity and associated inflammation with a compound of Formula A (e.g.,
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- C0105M) while Qin teaches that sepsis exacerbates microglia activation and neuroinflammation which have a negative impact on PD. The POSA would have done so to take advantage of the microglia-inhibiting anti-inflammatory effects of compounds of Formula A to counteract sepsis-induced microglia activation and neuroinflammation which have a negative impact in PD patients.
Claim 3 limits Claims 1, wherein said compound or pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition, wherein the compound is dissolved or dispersed in a pharmaceutically acceptable diluent. Barbier teaches effective amount of a compounds of the invention may be dissolved or dispersed in a physiologically tolerable carrier. See Claim 43.
Claims 8 and 9 narrows the structure and encompasses
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. Barbier teaches
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. See Claim 21 and Claim 46.
Claim 21 limits Claim 1, wherein said administration is carried out a plurality of times. Claim 22 limits Claim 1, wherein said administration is carried out daily. Claim 23 limits Claim 22, wherein said administration is carried out multiple times daily. Barbier teaches that the compounds of Formula A may be administered in a composition a plurality of times over a period of days (see Claim 48) or a plurality of times in one day (see Claim 49).
Claim 26, limits claim 1, wherein said hyperinflammatory syndrome is selected from one or more of the group consisting of cytokine storm, secondary hemophagocytic lymphohistiocytosis (sHLH), acute respiratory distress syndrome (ARDS), etc. Qin, while not explicitly mentioning the terms “hyperinflammatory syndrome” or “cytokine storm”, demonstrated systemic LPS (such as in the case of systemic infection with a gram negative bacteria) causes a cytokine storm by inducing an overactive immune response due to increased release of systemic cytokines (e.g., TNFα) such that self-propelling neuroinflammation results. Qin’s findings suggest that systemic LPS or TNFα activates brain microglia through TNFα receptors that initiate sustained activation of brain cytokine synthesis and neuroinflammation. See p. 5, last par.; see also p. 2, last par.; see also section under ‘Peripheral Inflammation Causes Chronic Neuroinflammation Through TNFα’ spanning pp. 6 and 7.
Response to arguments
Applicant argues that Liu does not teach a compound such as C0105M or activation mediated by RAGE/TLR2. Applicant further argues that Barbier does not teach inhibiting an immune response mediated by the specified cell surface receptors (e.g., RAGE/TLR2). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). While Liu does not expressly teach C0105M and Liu and Barbier do not teach activation by RAGE/TLR2 or inhibiting RAGE/TLR2-mediated immune response, Liu provides naloxone to bind FLNA to inhibit microglial activity and inflammation for treating PD. The C0105M compound is disclosed by Barbier as having similar activity as naloxone by binding FLNA and having anti-inflammatory effects. The receptor mechanism (RAGE/TLR2) involved in microglia activation and inflammation is provided by Han and sepsis association with microglia activation and inflammation exacerbating PD is provided by Qin. Thus, a POSA would have sought to reduce activation with a compound of Formula A (e.g., C0105M) as suggested above including activation mediated by TLR2 and/or RAGE and sepsis since these are involved in increasing microglial cell activity and said increased activity is pathologically linked to Parkinson’s disease.
Applicant argues that Barbier and Han do not teach a hyperinflammatory syndrome. Applicant further states that sepsis is not a hyperinflammatory syndrome. However, Claim 1’s definition of “hyperinflammatory syndrome” expressly includes sepsis, SIRS, hypotensive shock, etc. So by Applicant’s own construction, sepsis is squarely a hyperinflammatory syndrome. Furthermore, at the least, Qin, while not explicitly mentioning the terms “hyperinflammatory syndrome” or “cytokine storm”, demonstrated systemic LPS (such as in the case of systemic infection with a gram negative bacteria) causes a cytokine storm by inducing an overactive immune response due to increased release of systemic cytokines (e.g., TNFα) such that self-propelling neuroinflammation results.
Double Patenting
One rejection maintained
Several rejections are newly added
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.
A. Maintained - Claims 1, 3, 8, 9, 21-23, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 8,614,324 (reference) in view of Liu et al., Barbier et al. and Han et al. and Qin et al. (each cited above).
The reference claims are drawn to compounds of formula II which include compounds such as
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which is a species of instant claimed formula. The utility of the compound is to bind to FLNA and thereby inhibit inflammation. See reference specification at col. 5:57 to col. 6:2. Although the claims at issue are not identical, they are not patentably distinct from each other because the compounds of each claim set have the same utility of binding FLNA and inhibiting cell motility and inflammation.
The claim sets differ because the reference claims do not teach:
1) a compound of formula A such as
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2) the immune response is mediated by one or more of TLR2, RAGE, CCR5, CXCR4 and CD4, or
3) a hyperinflammatory syndrome such as sepsis or cytokine storm.
Regarding 1) a compound such as
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: It was already known that compounds of Formula A
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such as
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were similar to naloxone with FLNA binding properties and effectiveness in inhibiting inflammation in subjects. For example, Liu teaches that naloxone protects dopaminergic neurons against inflammatory damage in Parkinson’s disease (PD) by inhibiting microglia activation and superoxide generation, demonstrating the therapeutic benefit of suppressing microglial inflammatory responses. See title; abstract. Barbier teaches a method of reducing one or both of inflammation and pain in a host mammal by administering a composition containing a compound of Formula A
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such as
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(or a pharmaceutically acceptable salt thereof). See Barbier, Claim 21 and Claim 46. The compound binds to filamin A – FLNA; the high-affinity binding site of naloxone (NLX) and naltrexone (NTX) – to reduce cell motility and inflammation and prevent the Gi/o-to-Gs coupling switch of mu opioid receptor (MOR) and is similar to or more active than DAMGO in activating MOR. See Barbier, 0023; see also 0004-0005. The glial inflammatory response has been implicated in neuropathic pain as well as the inflammatory neurotoxicity of neurodegenerative disease. Barbier further teaches that femtomolar amounts of naloxone and its inactive isomer, both known to bind FLNA, have been shown to reduce the microglial inflammatory response; i.e., pro-inflammatory factors and reactive oxygen species, of lipopolysaccharide-activated microglial cells (citing Liu et al.). See Barbier, 0004. FLNA controls cell motility by controlling the cycle of actin polymerization and depolymerization, allowing cells to move and to migrate. As actin depolymerization is linked to the inflammatory response, binding to FLNA suppresses inflammation by slowing actin polymerization and cell motility. See Barbier, 0004.
One of ordinary skill in the art (POSA) would have found it obvious to use the reference compound such as the compound of Formula A,
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, to treat a subject with an inflammation condition such as Parkinson's disease (PD) because the reference teaches the compound,
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, has the utility of binding FLNA and inhibiting inflammation, while Liu teaches naloxone protects PD subjects by inhibiting microglial cell activity and associated inflammation and Barbier teaches that naloxone works by binding to FLNA and inhibiting microglial inflammatory response and further teaches that compounds of Formula A (e.g.,
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) act similar to naloxone by binding to FLNA and inhibiting cell motility and inflammatory activity. The POSA would have sought to take advantage of the similar FLNA-binding activity shared between the reference compounds that read on compounds of Formula A such as
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and naloxone in order to reduce inflammatory response by microglial cells in PD subjects because Liu teaches that naloxone treats PD by binding to FLNA and inhibiting microglial inflammatory response while Barbier also teaches that naloxone inhibits microglial response by binding FLNA and further teaches that compounds of Formula A such as
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works to inhibit inflammation in a similar fashion, i.e., binding FLNA.
Regarding 2) the immune response is mediated by one or more of TLR2, RAGE, CCR5, CXCR4 and CD4: It was already known that microglial cells are immune cells with TLR2 and RAGE receptors. Han teaches microglia are the immune effector cells of the central nervous system (CNS) after being activated. Microglia are involved in brain diseases such as brain injury, inflammation, multiple sclerosis, Alzheimer’s disease and recurrent seizures. Appropriate inhibition of microglial cell activation at the early stage can reduce the pathological damages caused by its activation. See 1st par., p. 57. Microglial cells express RAGE and TLR2 and have an increased expression of RAGE and TLR2 when activated. See p. 62-64; see also Figs. A and B.
One of ordinary skill in the art (POSA) would have found it obvious to inhibit activated microglial cells in order to reduce inflammatory damage induced by the activated microglial cells in PD subjects with a compound of formula A. Given that microglial cells are activated through TLR2 and/or RAGE, the POSA would have found it obvious to inhibit the microglial activation including activation mediated by TLR2 and/or RAGE. The POSA would have sought to reduce activation with a compound of Formula A as suggested above including activation mediated by TLR2 and/or RAGE since these are involved in increasing microglial cell activity and said increased activity is pathologically linked to Parkinson’s disease. Furthermore, the artisan would have a reasonable expectation of success that the administration of the compound to the subject would consequently lead to the administration to the microglial immune cell.
Regarding 3) the hyperinflammatory syndrome, e.g., sepsis or cytokine storm:
Sepsis was known to occur in PD patients and lead to progressive dopaminergic (DA) neurodegeneration, which exacerbates PD. For example, studies by Qin conducted with lipopolysaccharide (LPS, strain O111:B4 (E. coli strain) – see p. 3 ‘Reagents’) to induce an overactive inflammatory cytokine release, including peripheral TNFα, indicate that a single occurrence of sepsis and peripheral inflammation may result in self-propelling neuroinflammation and progressive DA neurodegeneration. See p. 2, last par.; see also three paragraphs under section ‘Peripheral Inflammation Causes Chronic Neuroinflammation Through TNFα’ spanning pp. 6 and 7; see also p. 5, last par. Qin teaches that LPS demonstrated that peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated proinflammatory factors; and (2) induce delayed and progressive loss of DA neurons in the SN. Qin’s findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease as systemic LPS causes neuroinflammation and progressive neurodegeneration. See title; abstract.
The POSA would have found it obvious to treat a PD patient with sepsis and overactive self-propelling neuroinflammatory response due to increased release of cytokines (e.g., TNFα), i.e., cytokine storm, with the claimed compound because Liu, Barbier and Han suggest treating PD by binding FLNA to decreasing microglia activity and associated inflammation with a compound of Formula A (e.g.,
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) while Qin teaches that sepsis exacerbates microglia activation and neuroinflammation which have a negative impact on PD. The POSA would have done so to take advantage of the microglia-inhibiting anti-inflammatory effects of compounds of Formula A to counteract sepsis-induced microglia activation and neuroinflammation which have a negative impact in PD patients.
Claim 3 limits Claims 1, wherein said compound or pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition, wherein the compound is dissolved or dispersed in a pharmaceutically acceptable diluent. Barbier teaches effective amount of a compounds of the invention may be dissolved or dispersed in a physiologically tolerable carrier. See Barbier, Claim 43.
Claims 8 and 9 narrows the structure and encompasses
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. Barbier and the reference claims teach
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. See Barbier, Claim 21 and Claim 46.
Claim 21 limits Claim 1, wherein said administration is carried out a plurality of times. Claim 22 limits Claim 1, wherein said administration is carried out daily. Claim 23 limits Claim 22, wherein said administration is carried out multiple times daily. Barbier teaches that the compounds of Formula A may be administered in a composition a plurality of times over a period of days (see Claim 48) or a plurality of times in one day (see Claim 49).
Claim 26, limits claim 1, wherein said hyperinflammatory syndrome is selected from one or more of the group consisting of cytokine storm, secondary hemophagocytic lymphohistiocytosis (sHLH), acute respiratory distress syndrome (ARDS), etc. Qin, while not explicitly mentioning the terms “hyperinflammatory syndrome” or “cytokine storm”, demonstrated systemic LPS (such as in the case of systemic infection with a gram negative bacteria) causes a cytokine storm by inducing an overactive immune response due to increased release of systemic cytokines (e.g., TNFα) such that self-propelling neuroinflammation results. Qin’s findings suggest that systemic LPS or TNFα activates brain microglia through TNFα receptors that initiate sustained activation of brain cytokine synthesis and neuroinflammation. See p. 5, last par.; see also p. 2, last par.; see also section under ‘Peripheral Inflammation Causes Chronic Neuroinflammation Through TNFα’ spanning pp. 6 and 7.
Response to arguments
The request the rejection be held in abeyance. The rejection is still deemed to be proper and is, therefore, maintained.
B. New rejection - Claims 1, 3, 8, 9, 21-23 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10,017,736 B2 (reference) in view of Liu et al., Barbier et al. and Han et al. and Qin et al. (each cited above).
The reference claims teach compounds of a formula that include compounds such as
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which is a species of the instant claimed formula. The utility of the compound is to bind to FLNA and thereby inhibit inflammation. See reference Abstract; see also col. 67:~22-25. Although the claims at issue are not identical, they are not patentably distinct from each other because the compounds of each claim set have the same utility of binding FLNA and inhibiting cell motility and inflammation.
The claim sets differ because the reference claims do not teach:
1) the immune response is mediated by one or more of TLR2, RAGE, CCR5, CXCR4 and CD4, or
2) a hyperinflammatory syndrome such as sepsis or cytokine storm.
Regarding 1) the immune response is mediated by one or more of TLR2, RAGE, CCR5, CXCR4 and CD4: It was already known that compounds such as
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were similar to naloxone with FLNA binding properties and effectiveness in inhibiting inflammation in subjects. For example, Liu teaches that naloxone protects dopaminergic neurons against inflammatory damage in Parkinson’s disease (PD) by inhibiting microglia activation and superoxide generation, demonstrating the therapeutic benefit of suppressing microglial inflammatory responses. See title; abstract. Barbier teaches a method of reducing one or both of inflammation and pain in a host mammal by administering a composition containing a compound of Formula A such as
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(or a pharmaceutically acceptable salt thereof). See Barbier, Claim 21 and Claim 46. The compound binds to filamin A – FLNA; the high-affinity binding site of naloxone (NLX) and naltrexone (NTX) – to reduce cell motility and inflammation and prevent the Gi/o-to-Gs coupling switch of mu opioid receptor (MOR) and is similar to or more active than DAMGO in activating MOR. See Barbier, 0023; see also 0004-0005. The glial inflammatory response has been implicated in neuropathic pain as well as the inflammatory neurotoxicity of neurodegenerative disease. Barbier further teaches that femtomolar amounts of naloxone and its inactive isomer, both known to bind FLNA, have been shown to reduce the microglial inflammatory response; i.e., pro-inflammatory factors and reactive oxygen species, of lipopolysaccharide-activated microglial cells (citing Liu et al.). See Barbier, 0004. FLNA controls cell motility by controlling the cycle of actin polymerization and depolymerization, allowing cells to move and to migrate. As actin depolymerization is linked to the inflammatory response, binding to FLNA suppresses inflammation by slowing actin polymerization and cell motility. See Barbier, 0004.
One of ordinary skill in the art (POSA) would have found it obvious to use the reference compound such as the compound of Formula A,
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, to treat a subject with an inflammation condition such as Parkinson's disease (PD) because the reference teaches the compound,
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, has the utility of binding FLNA and inhibiting inflammation, while Liu teaches naloxone protects PD subjects by inhibiting microglial cell activity and associated inflammation and Barbier teaches that naloxone works by binding to FLNA and inhibiting microglial inflammatory response and further teaches that compounds of Formula A (e.g.,
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) act similar to naloxone by binding to FLNA and inhibiting cell motility and inflammatory activity. The POSA would have sought to take advantage of the similar FLNA-binding activity shared between the reference compounds that read on compounds of Formula A such as
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and naloxone in order to reduce inflammatory response by microglial cells in PD subjects because Liu teaches that naloxone treats PD by binding to FLNA and inhibiting microglial inflammatory response while Barbier also teaches that naloxone inhibits microglial response by binding FLNA and further teaches that compounds of Formula A such as
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works to inhibit inflammation in a similar fashion, i.e., binding FLNA.
Regarding 2) the immune response is mediated by one or more of TLR2, RAGE, CCR5, CXCR4 and CD4: It was already known that microglial cells are immune cells with TLR2 and RAGE receptors. Han teaches microglia are the immune effector cells of the central nervous system (CNS) after being activated. Microglia are involved in brain diseases such as brain injury, inflammation, multiple sclerosis, Alzheimer’s disease and recurrent seizures. Appropriate inhibition of microglial cell activation at the early stage can reduce the pathological damages caused by its activation. See 1st par., p. 57. Microglial cells express RAGE and TLR2 and have an increased expression of RAGE and TLR2 when activated. See p. 62-64; see also Figs. A and B.
One of ordinary skill in the art (POSA) would have found it obvious to inhibit activated microglial cells in order to reduce inflammatory damage induced by the activated microglial cells in PD subjects with a compound of formula A. Given that microglial cells are activated through TLR2 and/or RAGE, the POSA would have found it obvious to inhibit the microglial activation including activation mediated by TLR2 and/or RAGE. The POSA would have sought to reduce activation with a compound of Formula A as suggested above including activation mediated by TLR2 and/or RAGE since these are involved in increasing microglial cell activity and said increased activity is pathologically linked to Parkinson’s disease. Furthermore, the artisan would have a reasonable expectation of success that the administration of the compound to the subject would consequently lead to the administration to the microglial immune cell.
Regarding 3) the hyperinflammatory syndrome, e.g., sepsis or cytokine storm:
Sepsis was known to occur in PD patients and lead to progressive dopaminergic (DA) neurodegeneration, which exacerbates PD. For example, studies by Qin conducted with lipopolysaccharide (LPS, strain O111:B4 (E. coli strain) – see p. 3 ‘Reagents’) to induce an overactive inflammatory cytokine release, including peripheral TNFα, indicate that a single occurrence of sepsis and peripheral inflammation may result in self-propelling neuroinflammation and progressive DA neurodegeneration. See p. 2, last par.; see also three paragraphs under section ‘Peripheral Inflammation Causes Chronic Neuroinflammation Through TNFα’ spanning pp. 6 and 7; see also p. 5, last par. Qin teaches that LPS demonstrated that peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated proinflammatory factors; and (2) induce delayed and progressive loss of DA neurons in the SN. Qin’s findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease as systemic LPS causes neuroinflammation and progressive neurodegeneration. See title; abstract.
The POSA would have found it obvious to treat a PD patient with sepsis and overactive self-propelling neuroinflammatory response due to increased release of cytokines (e.g., TNFα), i.e., cytokine storm, with the claimed compound because Liu, Barbier and Han suggest treating PD by binding FLNA to decreasing microglia activity and associated inflammation with a compound of Formula A (e.g.,
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) while Qin teaches that sepsis exacerbates microglia activation and neuroinflammation which have a negative impact on PD. The POSA would have done so to take advantage of the microglia-inhibiting anti-inflammatory effects of compounds of Formula A to counteract sepsis-induced microglia activation and neuroinflammation which have a negative impact in PD patients.
Claim 3 limits Claims 1, wherein said compound or pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition, wherein the compound is dissolved or dispersed in a pharmaceutically acceptable diluent. Barbier teaches effective amount of a compounds of the invention may be dissolved or dispersed in a physiologically tolerable carrier. See Barbier, Claim 43.
Claims 8 and 9 narrows the structure and encompasses
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. Barbier and the reference claims teach
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. See Barbier, Claim 21 and Claim 46.
Claim 21 limits Claim 1, wherein said administration is carried out a plurality of times. Claim 22 limits Claim 1, wherein said administration is carried out daily. Claim 23 limits Claim 22, wherein said administration is carried out multiple times daily. Barbier teaches that the compounds of Formula A may be administered in a composition a plurality of times over a period of days (see Claim 48) or a plurality of times in one day (see Claim 49).
Claim 26, limits claim 1, wherein said hyperinflammatory syndrome is selected from one or more of the group consisting of cytokine storm, secondary hemophagocytic lymphohistiocytosis (sHLH), acute respiratory distress syndrome (ARDS), etc. Qin, while not explicitly mentioning the terms “hyperinflammatory syndrome” or “cytokine storm”, demonstrated systemic LPS (such as in the case of systemic infection with a gram negative bacteria) causes a cytokine storm by inducing an overactive immune response due to increased release of systemic cytokines (e.g., TNFα) such that self-propelling neuroinflammation results. Qin’s findings suggest that systemic LPS or TNFα activates brain microglia through TNFα receptors that initiate sustained activation of brain cytokine synthesis and neuroinflammation. See p. 5, last par.; see also p. 2, last par.; see also section under ‘Peripheral Inflammation Causes Chronic Neuroinflammation Through TNFα’ spanning pp. 6 and 7.
C. New rejection - Claims 1, 3, 8, 9, 21-23 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10,760,052 B2 (reference) in view of Liu et al., Barbier et al. and Han et al. and Qin et al. (each cited above).
The reference claims teach compounds of a formula that include compounds such as
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which is a species of the instant claimed formula. The utility of the compound is to bind to FLNA and thereby inhibit inflammation. See reference Abstract; see also col. 68:~49-52. Although the claims at issue are not identical, they are not patentably distinct from each other because the compounds of each claim set have the same utility of binding FLNA and inhibiting cell motility and inflammation.
The claim sets differ because the reference claims do not teach:
1) the immune response is mediated by one or more of TLR2, RAGE, CCR5, CXCR4 and CD4, or
2) a hyperinflammatory syndrome such as sepsis or cytokine storm.
Regarding 1) the immune response is mediated by one or more of TLR2, RAGE, CCR5, CXCR4 and CD4: It was already known that compounds such as
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were similar to naloxone with FLNA binding properties and effectiveness in inhibiting inflammation in subjects. For example, Liu teaches that naloxone protects dopaminergic neurons against inflammatory damage in Parkinson’s disease (PD) by inhibiting microglia activation and superoxide generation, demonstrating the therapeutic benefit of suppressing microglial inflammatory responses. See title; abstract. Barbier teaches a method of reducing one or both of inflammation and pain in a host mammal by administering a composition containing a compound of Formula A such as
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(or a pharmaceutically acceptable salt thereof). See Barbier, Claim 21 and Claim 46. The compound binds to filamin A – FLNA; the high-affinity binding site of naloxone (NLX) and naltrexone (NTX) – to reduce cell motility and inflammation and prevent the Gi/o-to-Gs coupling switch of mu opioid receptor (MOR) and is similar to or more active than DAMGO in activating MOR. See Barbier, 0023; see also 0004-0005. The glial inflammatory response has been implicated in neuropathic pain as well as the inflammatory neurotoxicity of neurodegenerative disease. Barbier further teaches that femtomolar amounts of naloxone and its inactive isomer, both known to bind FLNA, have been shown to reduce the microglial inflammatory response; i.e., pro-inflammatory factors and reactive oxygen species, of lipopolysaccharide-activated microglial cells (citing Liu et al.). See Barbier, 0004. FLNA controls cell motility by controlling the cycle of actin polymerization and depolymerization, allowing cells to move and to migrate. As actin depolymerization is linked to the inflammatory response, binding to FLNA suppresses inflammation by slowing actin polymerization and cell motility. See Barbier, 0004.
One of ordinary skill in the art (POSA) would have found it obvious to use the reference compound such as the compound of Formula A,
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, to treat a subject with an inflammation condition such as Parkinson's disease (PD) because the reference teaches the compound,
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, has the utility of binding FLNA and inhibiting inflammation, while Liu teaches naloxone protects PD subjects by inhibiting microglial cell activity and associated inflammation and Barbier teaches that naloxone works by binding to FLNA and inhibiting microglial inflammatory response and further teaches that compounds of Formula A (e.g.,
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) act similar to naloxone by binding to FLNA and inhibiting cell motility and inflammatory activity. The POSA would have sought to take advantage of the similar FLNA-binding activity shared between the reference compounds that read on compounds of Formula A such as
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and naloxone in order to reduce inflammatory response by microglial cells in PD subjects because Liu teaches that naloxone treats PD by binding to FLNA and inhibiting microglial inflammatory response while Barbier also teaches that naloxone inhibits microglial response by binding FLNA and further teaches that compounds of Formula A such as
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works to inhibit inflammation in a similar fashion, i.e., binding FLNA.
Regarding 2) the immune response is mediated by one or more of TLR2, RAGE, CCR5, CXCR4 and CD4: It was already known that microglial cells are immune cells with TLR2 and RAGE receptors. Han teaches microglia are the immune effector cells of the central nervous system (CNS) after being activated. Microglia are involved in brain diseases such as brain injury, inflammation, multiple sclerosis, Alzheimer’s disease and recurrent seizures. Appropriate inhibition of microglial cell activation at the early stage can reduce the pathological damages caused by its activation. See 1st par., p. 57. Microglial cells express RAGE and TLR2 and have an increased expression of RAGE and TLR2 when activated. See p. 62-64; see also Figs. A and B.
One of ordinary skill in the art (POSA) would have found it obvious to inhibit activated microglial cells in order to reduce inflammatory damage induced by the activated microglial cells in PD subjects with a compound of formula A. Given that microglial cells are activated through TLR2 and/or RAGE, the POSA would have found it obvious to inhibit the microglial activation including activation mediated by TLR2 and/or RAGE. The POSA would have sought to reduce activation with a compound of Formula A as suggested above including activation mediated by TLR2 and/or RAGE since these are involved in increasing microglial cell activity and said increased activity is pathologically linked to Parkinson’s disease. Furthermore, the artisan would have a reasonable expectation of success that the administration of the compound to the subject would consequently lead to the administration to the microglial immune cell.
Regarding 3) the hyperinflammatory syndrome, e.g., sepsis or cytokine storm:
Sepsis was known to occur in PD patients and lead to progressive dopaminergic (DA) neurodegeneration, which exacerbates PD. For example, studies by Qin conducted with lipopolysaccharide (LPS, strain O111:B4 (E. coli strain) – see p. 3 ‘Reagents’) to induce an overactive inflammatory cytokine release, including peripheral TNFα, indicate that a single occurrence of sepsis and peripheral inflammation may result in self-propelling neuroinflammation and progressive DA neurodegeneration. See p. 2, last par.; see also three paragraphs under section ‘Peripheral Inflammation Causes Chronic Neuroinflammation Through TNFα’ spanning pp. 6 and 7; see also p. 5, last par. Qin teaches that LPS demonstrated that peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated proinflammatory factors; and (2) induce delayed and progressive loss of DA neurons in the SN. Qin’s findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease as systemic LPS causes neuroinflammation and progressive neurodegeneration. See title; abstract.
The POSA would have found it obvious to treat a PD patient with sepsis and overactive self-propelling neuroinflammatory response due to increased release of cytokines (e.g., TNFα), i.e., cytokine storm, with the claimed compound because Liu, Barbier and Han suggest treating PD by binding FLNA to decreasing microglia activity and associated inflammation with a compound of Formula A (e.g.,
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) while Qin teaches that sepsis exacerbates microglia activation and neuroinflammation which have a negative impact on PD. The POSA would have done so to take advantage of the microglia-inhibiting anti-inflammatory effects of compounds of Formula A to counteract sepsis-induced microglia activation and neuroinflammation which have a negative impact in PD patients.
Claim 3 limits Claims 1, wherein said compound or pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition, wherein the compound is dissolved or dispersed in a pharmaceutically acceptable diluent. Barbier teaches effective amount of a compounds of the invention may be dissolved or dispersed in a physiologically tolerable carrier. See Barbier, Claim 43.
Claims 8 and 9 narrows the structure and encompasses
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