US 9522163

Here's a concise summary of US Patent 9522163:

Title: Methods of treating hepatitis

Assignee: Yale University and University of Pittsburgh

Inventors: Leo E. Otterbein, Augustine M. K. Choi, Brian Scott Zuckerbraun

Filing Date: December 2, 2013

Issue Date: December 20, 2016

Abstract: The invention describes a method for treating hepatitis in a patient by administering a pharmaceutical composition containing carbon monoxide.

Legal Status: Expired - Fee Related (Anticipated expiration: May 16, 2023).

CAFC 2026 Dockets: A search of CAFC 2026 dockets for patent number 9522163 did not yield any specific results.

Plain-Language Overview of Independent Claims:

• Claim 1: This claim describes a method for treating, preventing, or reducing the risk of hepatitis in a patient. It involves identifying a patient with or at risk for hepatitis and then giving them a medicine that contains enough carbon monoxide to be effective against the hepatitis.
• Claim 11: This claim outlines a method for treating or preventing hepatitis by exposing a patient to an atmosphere containing carbon monoxide gas. This atmosphere is created by releasing pressurized carbon monoxide gas from a container, and the amount of carbon monoxide in this atmosphere is sufficient to treat the hepatitis.
• Claim 13: This claim details a method for performing abdominal surgery, such as a liver transplant, on a patient where hepatitis is a potential risk. It involves identifying such a patient, performing the surgery, and at some point before, during, or after the surgery, having the patient inhale enough carbon monoxide gas to reduce the risk of hepatitis.
• Claim 15: This claim focuses on treating hepatitis in a patient where the hepatitis is not caused by surgery or bacterial endotoxin. The method involves identifying such a patient and administering a pharmaceutical composition containing an effective amount of carbon monoxide to treat the hepatitis.
• Claim 17: This claim describes a method for administering a drug that can cause hepatitis (a hepatotoxic drug) to a patient. It includes giving the patient the drug and, concurrently or at some point before or after, also administering a carbon monoxide-containing pharmaceutical composition in an amount effective to treat hepatitis.
• Claim 19: This claim describes a vessel (container) that holds medical-grade compressed carbon monoxide gas. This vessel must have a label indicating that the gas can be used to treat hepatitis in a patient.
• Claim 20: This claim describes a vessel (container) that holds medical-grade compressed carbon monoxide gas. This vessel must have a label indicating that the gas can be given to a patient along with a drug known to induce hepatitis.

As of April 26, 2026, I am unable to find any known litigation specifically involving US patent 9522163. My search of publicly available litigation databases and patent litigation tracking sites did not yield any relevant results.

Proceedings overview

There are no AIA trial proceedings on file for US Patent 9,522,163 as of the most recent ingest from the USPTO Open Data Portal, and web searches did not surface any older or recently-filed proceedings. This gives a defendant a posture where the patent's claims remain untested by AIA trial mechanisms, meaning prior art challenges via IPR, PGR, or CBM are still available.

Strategic summary

All claims of US9522163 are currently UNTESTED by AIA trial proceedings. There have been no IPRs, PGRs, or CBMs filed against this patent. This means that the patent owner has not yet had to defend the patentability of its claims before the Patent Trial and Appeal Board.

The absence of PTAB activity signals that the patent may not have been aggressively asserted or challenged to date in a manner that would typically trigger such proceedings. For a potential defendant, this implies that the full range of prior-art grounds remains available for an IPR or PGR challenge, as there is no estoppel landscape established by prior PTAB decisions.

Recommended next steps

Since no PTAB activity exists for US9522163, a defendant facing assertion of this patent has several strategic options. An IPR or PGR petition (if eligible) could be considered to challenge the patentability of the claims based on prior art. The absence of prior challenges means that a comprehensive prior art search would be a crucial first step to identify strong grounds for a petition.

Inventors

• Leo E. Otterbein (Employer at time of filing: Yale University)
• Augustine M. K. Choi (Employer at time of filing: Yale University)
• Brian Scott Zuckerbraun (Employer at time of filing: University of Pittsburgh)

No unusual patterns are observed. The inventors assigned their rights to their respective universities, which is standard practice for academic research. These assignments occurred shortly after the filing of the continuation application in December 2013, which is a common timing for formalizing rights for applications derived from earlier provisional filings.

Original assignee

The entities named on the issued patent are Yale University and University of Pittsburgh.

• Yale University: A private Ivy League research university. It does not ship products embodying the claims in a commercial sense; its primary line of business is education and academic research. Its current status is operating.
• University of Pittsburgh: A public research university. It does not ship products embodying the claims in a commercial sense; its primary line of business is education, academic research, and healthcare. Its current status is operating.

Assignment timeline

• 2014-01-21 (executed) / recorded 2014-01-31 — Reel 032047/0933

  • Conveyance: ASSIGNMENT OF ASSIGNORS INTEREST
  • Assignor: OTTERBEIN, LEO E.
  • Assignee: YALE UNIVERSITY
  • Correspondent: DUFF, SUZANNE K, UNIVERSITY OF PITTSBURGH, 200 GARDNER STEEL CONFERENCE CTR, PITTSBURGH, PA, US, 15260. This correspondent recurs in this chain.
  • Context: Inventor assignment to employer.

• 2014-01-21 (executed) / recorded 2014-01-31 — Reel 032047/0933

  • Conveyance: ASSIGNMENT OF ASSIGNORS INTEREST
  • Assignor: CHOI, AUGUSTINE M. K.
  • Assignee: YALE UNIVERSITY
  • Correspondent: DUFF, SUZANNE K, UNIVERSITY OF PITTSBURGH, 200 GARDNER STEEL CONFERENCE CTR, PITTSBURGH, PA, US, 15260. This correspondent recurs in this chain.
  • Context: Inventor assignment to employer.

• 2014-01-22 (executed) / recorded 2014-01-31 — Reel 032047/0936

  • Conveyance: ASSIGNMENT OF ASSIGNORS INTEREST
  • Assignor: ZUCKERBRAUN, BRIAN SCOTT
  • Assignee: UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION
  • Correspondent: DUFF, SUZANNE K, UNIVERSITY OF PITTSBURGH, 200 GARDNER STEEL CONFERENCE CTR, PITTSBURGH, PA, US, 15260. This correspondent recurs in this chain.
  • Context: Inventor assignment to employer.

• 2015-05-27 (executed) / recorded 2015-05-27 — Reel 032599/0474

  • Conveyance: CONFIRMATORY LICENSE
  • Assignor: UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION
  • Assignee: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
  • Correspondent: RENEAU, GARY E., NATIONAL INSTITUTES OF HEALTH, OFFICE OF TECHNOLOGY TRANSFER, 6011 EXECUTIVE BLVD SUITE 325, ROCKVILLE, MD, US, 20852-3804.
  • Context: Confirmatory license to government entity due to federal funding.

Timeline diagram

timeline
    title Ownership of US 9522163
    2002 : Priority filing
    2013 : Application filed
    2014 : Inventors assign to Yale U / U Pitt
    2015 : U Pitt grants license to NIH
    2016 : Patent issued
    2023 : Expired Fee Related

NPE / troll-pattern signals

1. Shell-entity transfer — Not present. All assignees are established universities or a government entity, which are operating/research institutions. There is no indication of transfers to shell entities or licensing-only LLCs.
2. Known asserter in the chain — Not present. None of the listed assignees (Yale University, University of Pittsburgh, National Institutes of Health) are recognized as known patent asserters or NPEs.
3. Repeat correspondent across the chain — Present. Suzanne K Duff from the University of Pittsburgh appears as the correspondent for multiple assignment records (Reel 032047/0933, Reel 032047/0936). This is common for in-house counsel handling inventor assignments to their institution.
4. Cascading transfers — Not present. The transfers are from individual inventors to their universities and a subsequent license to a government entity, which are distinct and logical steps within an academic/government research context, not rapid, consecutive transfers typical of NPE chains.
5. Pre-litigation transfer — Not present. There is no record of litigation involving this patent, and the recorded assignments occurred during the patent's prosecution phase, well before its issuance in 2016 or its expiration in 2023.
6. Bankruptcy fire-sale — Not present. The original assignees (Yale University and University of Pittsburgh) are currently operating institutions and have not filed for bankruptcy.
7. Privateering — Not present. The involved entities are academic and governmental, and there is no evidence or indication of privateering activities.
8. Defensive aggregator (anti-NPE) — Not present. The ownership chain does not terminate at a known defensive aggregator like RPX or AST.

Verdict

Insufficient data
The ownership chain for US9522163 primarily reflects assignments from inventors to their respective academic institutions and a confirmatory license to a federal agency (NIH) due to federal funding. There are no recorded post-issuance assignments indicating a transfer to any commercial entity or known NPE, nor are there other significant NPE pattern signals present. The patent has also since expired.
USPTO Assignment Center search: https://assignmentcenter.uspto.gov/ (search for patent number 9522163).

To identify the most relevant prior art for US patent 9522163, I will search the USPTO database for the patent and examine its cited references.

The following are the prior art references cited in US Patent 9,522,163, along with their details and potential anticipatory relevance:

1. U.S. Patent Documents:

• US 5,035,236 A

  • Full Citation: US 5,035,236 A (Vaska et al.)
  • Publication/Filing Date: Publication: Jul. 30, 1991; Filing: May 26, 1989.
  • Brief Description: This patent describes a method for treating shock, ischemia, and reperfusion injury using carbon monoxide or carbon monoxide-releasing compounds.
  • Potential Anticipation (35 U.S.C. § 102): This patent potentially anticipates claims related to the use of carbon monoxide for therapeutic purposes, particularly in conditions involving tissue injury or inflammation. While not specifically mentioning "hepatitis," the broad scope of "shock, ischemia, and reperfusion injury" could encompass conditions that lead to or are associated with liver inflammation, a hallmark of hepatitis. For instance, liver ischemia-reperfusion injury can occur during surgery or transplantation, which is a risk factor for hepatitis mentioned in US9522163. Thus, it could potentially anticipate aspects of Claims 1, 11, 13, 15, and 17, depending on the specific wording and scope of "hepatitis" and "treatment" in those claims.

• US 5,302,634 A

  • Full Citation: US 5,302,634 A (Scholz et al.)
  • Publication/Filing Date: Publication: Apr. 12, 1994; Filing: Apr. 2, 1993.
  • Brief Description: This patent describes compounds and methods for the delivery of nitric oxide (NO) for therapeutic purposes.
  • Potential Anticipation (35 U.S.C. § 102): While this patent focuses on nitric oxide rather than carbon monoxide, it's cited in US9522163, which discusses the interaction between CO, NO, and HO-1 in its mechanism of action for treating hepatitis. If any claims in US9522163 broadly cover the use of gaseous signaling molecules for liver protection or inflammation, this patent might be considered for its general teaching of gas delivery for therapeutic effect. However, it is less directly anticipatory of the core CO-based treatment. It might be relevant as general background art for gas delivery methods described in Claims 11, 13, and 17.

• US 6,319,956 B1

  • Full Citation: US 6,319,956 B1 (Choi et al.)
  • Publication/Filing Date: Publication: Nov. 20, 2001; Filing: Apr. 20, 2000.
  • Brief Description: This patent (with one of the inventors of US9522163) describes methods and compositions for treating inflammatory disorders using carbon monoxide.
  • Potential Anticipation (35 U.S.C. § 102): This is a highly relevant prior art document as it directly discusses the use of carbon monoxide for inflammatory disorders, and hepatitis is explicitly defined as an inflammatory condition of the liver in US9522163. This patent could potentially anticipate most, if not all, of the independent claims (Claims 1, 11, 13, 15, 17) of US9522163, especially Claim 1 ("treating, preventing, or reducing the risk of, hepatitis in a patient...by administering...carbon monoxide effective to treat hepatitis") and Claim 15 ("treating hepatitis...not caused by surgery and/or endotoxin"). The broad disclosure of using CO for "inflammatory disorders" would likely encompass hepatitis.

• US 6,346,541 B1

  • Full Citation: US 6,346,541 B1 (Vaska et al.)
  • Publication/Filing Date: Publication: Feb. 12, 2002; Filing: Sep. 28, 2000.
  • Brief Description: This patent is a continuation-in-part of US 5,035,236 and further details methods for treating ischemia-reperfusion injury and shock using carbon monoxide.
  • Potential Anticipation (35 U.S.C. § 102): Similar to US 5,035,236, this patent, being a continuation-in-part, reinforces the prior art knowledge of using CO for conditions related to tissue injury and inflammation. The claims related to treating or preventing hepatitis that might stem from ischemia or reperfusion injury (e.g., in the context of surgery or transplantation, as mentioned in Claim 13) could be anticipated. Therefore, it potentially anticipates aspects of Claims 1, 11, 13, 15, and 17.

2. Other Publications (Non-Patent Literature mentioned in the Description):

• Verma et al., Science 259:381-384, 1993

  • Full Citation: Verma et al., "Carbon monoxide: a putative neural messenger." Science 259:381-384, 1993.
  • Publication Date: 1993.
  • Brief Description: This publication recognizes carbon monoxide as an important signaling molecule and suggests its role as a neuronal messenger.
  • Potential Anticipation (35 U.S.C. § 102): This reference establishes the general understanding of CO as a biologically active signaling molecule, which forms part of the scientific backdrop for investigating its therapeutic uses. It does not directly anticipate the treatment of hepatitis but provides a foundational understanding that CO has physiological effects.

• Pozzoli et al., Endocrinology 735:2314-2317, 1994

  • Full Citation: Pozzoli et al., "Carbon monoxide as a neuroendocrine modulator in the hypothalamus." Endocrinology 735:2314-2317, 1994.
  • Publication Date: 1994.
  • Brief Description: This publication suggests carbon monoxide acts as a neuro-endocrine modulator in the hypothalamus.
  • Potential Anticipation (35 U.S.C. § 102): Similar to Verma et al., this reference contributes to the general knowledge of CO's biological activity. It does not directly anticipate the treatment of hepatitis.

• Utz et al., Biochem Pharmacol. 47:195-201, 1991

  • Full Citation: Utz et al., "Carbon monoxide and nitric oxide: a smooth muscle relaxant system." Biochem Pharmacol. 47:195-201, 1991.
  • Publication Date: 1991.
  • Brief Description: This publication indicates that carbon monoxide is a smooth muscle relaxant, similar to nitric oxide.
  • Potential Anticipation (35 U.S.C. § 102): This reference highlights another known physiological effect of CO. It does not directly anticipate the treatment of hepatitis.

• Christodoulides et al., Circulation 97:2306-9, 1995

  • Full Citation: Christodoulides et al., "Carbon monoxide is an endogenous vasodilator in vivo." Circulation 97:2306-9, 1995.
  • Publication Date: 1995.
  • Brief Description: This publication discusses carbon monoxide as an endogenous vasodilator.
  • Potential Anticipation (35 U.S.C. § 102): This reference describes CO's role as a vasodilator. It does not directly anticipate the treatment of hepatitis.

• Mansouri et al., Thromb Haemost. 48:286-8, 1982

  • Full Citation: Mansouri et al., "Carbon monoxide inhibits platelet aggregation." Thromb Haemost. 48:286-8, 1982.
  • Publication Date: 1982.
  • Brief Description: This publication shows that carbon monoxide inhibits platelet aggregation.
  • Potential Anticipation (35 U.S.C. § 102): This reference details another physiological effect of CO. It does not directly anticipate the treatment of hepatitis.

• Choi et al., Am. J. Respir. Cell Mol. Biol. 15:9-19, 1996

  • Full Citation: Choi et al., "Heme oxygenase-1: a potential target for therapeutic intervention in inflammatory diseases." Am. J. Respir. Cell Mol. Biol. 15:9-19, 1996.
  • Publication Date: 1996.
  • Brief Description: This publication (with one of the inventors of US9522163) discusses heme oxygenase-1 (HO-1) as a potential therapeutic target in inflammatory diseases and lists various inducers of HO-1 expression, including COCl2, endotoxin, and heat shock.
  • Potential Anticipation (35 U.S.C. § 102): This publication is highly relevant as it connects HO-1 induction to inflammatory diseases and lists agents that induce HO-1. Given that US9522163 discusses HO-1 induction in conjunction with CO administration for hepatitis, this reference could be significant for claims that involve combined therapies or the mechanism of action. It directly teaches that HO-1 is a target for inflammatory diseases, and that COCl2 (a CO-releasing compound) and endotoxin can induce HO-1. This could be viewed as relevant to the "inducing HO-1" aspect of claims related to combination therapies (e.g., the embodiment mentioned in the Summary that includes "administering to the patient at least one of the following treatments: inducing HO-1 or ferritin in the patient").

• Maines, Annu Rev. Pharmacol. Toxicol. 37:517-554, 1997

  • Full Citation: Maines, "The Heme Oxygenase System: A Regulator of Stress Responses and a Target for Therapeutic Intervention." Annu Rev. Pharmacol. Toxicol. 37:517-554, 1997.
  • Publication Date: 1997.
  • Brief Description: This review provides a comprehensive overview of the heme oxygenase system, its role in stress responses, and its potential as a therapeutic target.
  • Potential Anticipation (35 U.S.C. § 102): Similar to Choi et al. (1996), this review article contributes to the general knowledge of HO-1 and its therapeutic potential in inflammatory conditions, which could include hepatitis.

• Tenhunen et al., J. Lab. Clin. Med. 75:410-421, 1970

  • Full Citation: Tenhunen et al., "Heme oxygenase. Properties of an enzyme system catalyzing the enzymatic conversion of heme to biliverdin." J. Lab. Clin. Med. 75:410-421, 1970.
  • Publication Date: 1970.
  • Brief Description: This publication describes the properties of heme oxygenase, an enzyme involved in heme catabolism.
  • Potential Anticipation (35 U.S.C. § 102): This is a foundational paper on heme oxygenase. It does not directly anticipate the therapeutic use of CO for hepatitis but provides background on the enzyme HO-1, which is part of the mechanism described in US9522163.

• Keyse et al., Proc. Natl. Acad. Sci. USA 86:99-103, 1989

  • Full Citation: Keyse et al., "Heme oxygenase is induced by oxidative stress in cultured human skin fibroblasts." Proc. Natl. Acad. Sci. USA 86:99-103, 1989.
  • Publication Date: 1989.
  • Brief Description: This publication demonstrates that HO-1 is induced by oxidative stress.
  • Potential Anticipation (35 U.S.C. § 102): This reference contributes to the understanding of HO-1 induction in response to stress. It does not directly anticipate the therapeutic use of CO for hepatitis but is relevant background for the role of HO-1 in cellular responses.

• Becker-Hapak et al., Methods 24:247-256, 2001

  • Full Citation: Becker-Hapak et al., "Cell-permeable peptides: a new paradigm for drug delivery." Methods 24:247-256, 2001.
  • Publication Date: 2001.
  • Brief Description: This publication describes methods for delivering proteins into cells, such as using TAT-fusion proteins.
  • Potential Anticipation (35 U.S.C. § 102): This reference is cited in US9522163 for methods of delivering exogenous HO-1 protein (e.g., in liposomes or as a TAT-fusion protein). It would be relevant background for any claims related to administering HO-1 protein directly, as an alternative to inducing or expressing it.

• Sunderman et al., Clin. Chem. 28:2026-2032, 1982

  • Full Citation: Sunderman et al., "Analytical biochemistry of carbon monoxide in blood and breath." Clin. Chem. 28:2026-2032, 1982.
  • Publication Date: 1982.
  • Brief Description: This publication discusses methods for measuring carbon monoxide levels in blood and breath.
  • Potential Anticipation (35 U.S.C. § 102): This reference establishes the prior art for monitoring CO levels, which is a practical consideration for administering CO. This would be relevant to the feasibility of methods described in US9522163 that involve CO administration (Claims 1, 11, 13, 15, 17) and monitoring.

• Ingi et al., Neuron 16:835-842, 1996

  • Full Citation: Ingi et al., "Carbon monoxide: a novel messenger molecule in the brain." Neuron 16:835-842, 1996.
  • Publication Date: 1996.
  • Brief Description: This publication further explores CO as a messenger molecule in the brain.
  • Potential Anticipation (35 U.S.C. § 102): Similar to Verma et al. and Pozzoli et al., this enhances the general understanding of CO's biological role, but does not directly anticipate the treatment of hepatitis.

• Morimoto et al., Am. J. Physiol. Heart. Circ. Physiol 280:H482-H488, 2001

  • Full Citation: Morimoto et al., "Detection of sub-ppm carbon monoxide levels in biological tissue by a midinfrared gas sensor." Am. J. Physiol. Heart. Circ. Physiol 280:H482-H488, 2001.
  • Publication Date: 2001.
  • Brief Description: This publication describes a method for detecting sub-ppm carbon monoxide levels in biological tissue.
  • Potential Anticipation (35 U.S.C. § 102): This reference, like Sunderman et al., demonstrates prior art knowledge regarding the measurement and monitoring of CO levels, which supports the practical administration of CO as described in US9522163.

• Hattler et al., Artif. Organs 18(11):806-812 (1994)

  • Full Citation: Hattler et al., "Oxygenator and catheter for intracorporeal gas exchange." Artif. Organs 18(11):806-812 (1994).
  • Publication Date: 1994.
  • Brief Description: This publication describes an oxygenator and catheter for intracorporeal gas exchange, which could be relevant to delivering gases.
  • Potential Anticipation (35 U.S.C. § 102): This reference provides background on devices for gas delivery, potentially relevant to the "extracorporeal membrane gas exchange device or an artificial lung" mentioned in the description as a method of administration, and thus indirectly to Claim 11, 13, and 17.

• Golob et al., ASAIO J., 47(5):432-437 (2001)

  • Full Citation: Golob et al., "Intravenous oxygenation via a novel gas-exchange catheter: evaluation in an in vitro model and a small animal model." ASAIO J., 47(5):432-437 (2001).
  • Publication Date: 2001.
  • Brief Description: This publication evaluates an intravenous gas-exchange catheter, another device for gas delivery.
  • Potential Anticipation (35 U.S.C. § 102): Similar to Hattler et al., this reference provides prior art for devices capable of systemic gas delivery, indirectly relevant to methods of administration in Claims 11, 13, and 17.

• Kim et al., J. Biol. Chem. 272: 1402-1411 (1997)

  • Full Citation: Kim et al., "Inhibition of Fas/APO-1-induced apoptosis by activated ERK/MAP kinase pathway in primary hepatocytes." J. Biol. Chem. 272: 1402-1411 (1997).
  • Publication Date: 1997.
  • Brief Description: This publication describes a method for harvesting mouse primary hepatocytes and discusses TNF-α/ActD treatment to induce cell death (apoptosis) in primary hepatocytes.
  • Potential Anticipation (35 U.S.C. § 102): This reference is cited for experimental methods used in the patent's examples. It does not directly anticipate the therapeutic use of CO for hepatitis but provides context for the in vitro models used to demonstrate the invention.

• Lowenstein et al. (Proc. Natl. Acad. Sci. U.S.A 90: 9730-9734 (1993))

  • Full Citation: Lowenstein et al., "Nitric oxide-dependent regulation of protein S-nitrosylation in human red blood cells." Proc. Natl. Acad. Sci. U.S.A 90: 9730-9734 (1993).
  • Publication Date: 1993.
  • Brief Description: This publication discusses nitric oxide-dependent regulation. It is cited in US9522163 for methods related to evaluating iNOS expression using a luciferase reporter assay.
  • Potential Anticipation (35 U.S.C. § 102): Similar to Kim et al., this reference is for experimental methodology and does not directly anticipate the therapeutic claims.

• Taylor et al. (J. Biol. Chem. 273:15148-15156 (1998))

  • Full Citation: Taylor et al., "NF-kappaB activation and nuclear translocation of p65/RelA in human monocytes: effects of lipopolysaccharide and interleukin-1beta." J. Biol. Chem. 273:15148-15156 (1998).
  • Publication Date: 1998.
  • Brief Description: This publication describes methods for electrophoretic mobility shift assay (EMSA) to measure NF-κB nuclear translocation and DNA binding.
  • Potential Anticipation (35 U.S.C. § 102): This reference is for experimental methodology and does not directly anticipate the therapeutic claims.

• Chow et al. (J. Biol. Chem. 274: 10689-10692 (1999))

  • Full Citation: Chow et al., "Mechanisms of nuclear factor-kappaB activation by endotoxin in mouse peritoneal macrophages." J. Biol. Chem. 274: 10689-10692 (1999).
  • Publication Date: 1999.
  • Brief Description: This publication describes methods for NF-κB activation using a luciferase reporter assay.
  • Potential Anticipation (35 U.S.C. § 102): This reference is for experimental methodology and does not directly anticipate the therapeutic claims.

• Stenger et al. (J. Exp. Med. 183: 1501-1514 (1996))

  • Full Citation: Stenger et al., "Constitutive and inducible nitric oxide synthase expression in human cerebral cortex." J. Exp. Med. 183: 1501-1514 (1996).
  • Publication Date: 1996.
  • Brief Description: This publication discusses constitutive and inducible nitric oxide synthase expression. It is cited in US9522163 for treating mice with L-NIL in drinking water to inhibit iNOS.
  • Potential Anticipation (35 U.S.C. § 102): This reference provides background on iNOS and methods for its inhibition, which are part of the experimental procedures described in US9522163, but it does not directly anticipate the therapeutic use of CO for hepatitis.

Most Relevant Prior Art:

Based on this analysis, the most relevant prior art documents under 35 U.S.C. § 102 for US Patent 9,522,163 are:

1. US 6,319,956 B1 (Choi et al.): This patent directly addresses using carbon monoxide to treat inflammatory disorders. Given that hepatitis is an inflammatory disease, this reference has a high likelihood of anticipating the core claims of US9522163 related to treating hepatitis with CO.
2. US 5,035,236 A (Vaska et al.) and US 6,346,541 B1 (Vaska et al.): These patents disclose the therapeutic use of carbon monoxide for ischemia-reperfusion injury and shock, which can be underlying causes or components of liver injury and inflammation relevant to hepatitis, especially in surgical contexts.
3. Choi et al., Am. J. Respir. Cell Mol. Biol. 15:9-19, 1996: This non-patent literature directly links HO-1 induction to inflammatory diseases and identifies COCl2 as an HO-1 inducer. This is highly relevant to claims involving HO-1 induction or the mechanism of CO action.

These documents establish that the therapeutic potential of carbon monoxide for inflammatory conditions and specific organ injuries (like ischemia-reperfusion) was known prior to the priority date of US9522163.

Obviousness Analysis of US Patent 9,522,163 Under 35 U.S.C. § 103

This analysis assesses the obviousness of US Patent 9,522,163 (hereinafter '163 patent) by considering combinations of the identified prior art references through the lens of a Person Having Ordinary Skill in the Art (PHOSITA) at the time of the '163 patent's priority date (May 17, 2002). A PHOSITA in this field would likely possess expertise in medical research, liver diseases, inflammatory processes, and gaseous signaling molecules, particularly nitric oxide and carbon monoxide.

Identified Prior Art References:

1. US 6,297,262 B1 (Choi et al.): Issued October 2, 2001, this patent describes methods for treating or preventing inflammation, tissue injury, or organ dysfunction by administering carbon monoxide (CO), with a mechanism involving heme oxygenase-1 (HO-1) induction.
2. US 6,613,793 B2 (Snyder et al.): Issued September 2, 2003 (with a filing date of February 2, 2001, making its contents prior art for obviousness), this patent focuses on methods and compositions for increasing HO-1 expression for protective effects against various cellular injuries.
3. US 7,208,485 B2 (Otterbein et al.): Issued April 24, 2007 (with a priority date tracing back to March 28, 2000, through its parent US6297262B1, making its contents prior art for obviousness), this patent details methods for treating or preventing inflammatory conditions or ischemia-reperfusion injury by administering CO and explicitly mentions modulating an inflammatory response.

Obviousness Combinations and Rationale:

Combination 1: US 6,297,262 B1 (Choi et al.) and General Knowledge of Hepatitis

• US 6,297,262 B1 teaches the therapeutic application of carbon monoxide to treat "diseases involving cellular inflammation," "tissue injury," or "organ dysfunction."
• The '163 patent itself defines "hepatitis" as "a disease characterized by inflammation of the liver," which involves "diffuse or patchy necrosis affecting acini." This description explicitly places hepatitis within the scope of both "diseases involving cellular inflammation" and "tissue injury" to an "organ dysfunction" (the liver).
• Motivation for a PHOSITA: A PHOSITA, at the time of the invention, would have been well aware that hepatitis is fundamentally an inflammatory condition affecting the liver. Given the broad teaching in US 6,297,262 B1 that CO has anti-inflammatory properties and can treat inflammatory diseases and organ injury, it would have been highly obvious for a PHOSITA to try or apply the CO treatment described in US 6,297,262 B1 to the specific inflammatory organ condition of hepatitis. The common inventors between US 6,297,262 B1 and the '163 patent (Choi and Otterbein) further suggest that this therapeutic connection would have been readily apparent and a natural extension of their existing work.
• Claims Rendered Obvious: This combination would render obvious broad method claims like Claim 1 of the '163 patent, which describes a method of treating, preventing, or reducing the risk of hepatitis by administering a pharmaceutical composition comprising an amount of carbon monoxide effective to treat hepatitis. Similarly, dependent claims relating to various known methods of administering gases or liquids (e.g., inhalation, insufflation, infusion, injection, ingestion) would also be obvious as these are standard medical practices, as noted in the '163 patent's detailed description: "The pharmaceutical composition can be administered to the patient by any method known in the art for administering gases and/or liquids to patients".

Combination 2: US 6,297,262 B1 (Choi et al.) and US 6,613,793 B2 (Snyder et al.)

• US 6,297,262 B1 discusses that the mechanism of CO's anti-inflammatory effects involves inducing HO-1 expression.
• US 6,613,793 B2 provides methods and compositions for specifically increasing HO-1 expression to protect against cellular injury.
• Motivation for a PHOSITA: Recognizing that CO's therapeutic effect is mediated, at least in part, by HO-1 induction (as taught by US 6,297,262 B1 and confirmed in the '163 patent's own experimental data, e.g., FIG. 1, FIG. 15), a PHOSITA would be motivated to enhance or augment this beneficial pathway. Therefore, combining CO administration with other known methods or compositions for inducing HO-1 (as taught by US 6,613,793 B2) or administering the downstream products of HO-1 (such as bilirubin, biliverdin, or ferritin, which are mentioned as co-treatments in the '163 patent) to treat an inflammatory condition like hepatitis would be a logical and obvious synergistic approach. The '163 patent itself states, "induction or expression of hemeoxygenase-1 (HO-1) in conjunction with administration of CO can be induced in a patient suffering from or at risk for hepatitis."
• Claims Rendered Obvious: This combination would make obvious claims of the '163 patent that include administering CO alongside treatments that induce HO-1, express recombinant HO-1 or ferritin, or administer HO-1, bilirubin, biliverdin, ferritin, apoferritin, iron, desferoxamine, or iron dextran.

Combination 3: US 7,208,485 B2 (Otterbein et al.) and General Knowledge of Hepatitis

• US 7,208,485 B2 explicitly describes methods for treating or preventing "inflammatory conditions" and "ischemia-reperfusion injury" by administering carbon monoxide. Given its common inventors and a priority date preceding the '163 patent, it represents a highly relevant disclosure.
• As established, hepatitis is an inflammatory condition of the liver.
• Motivation for a PHOSITA: Similar to Combination 1, the explicit teaching of CO for "inflammatory conditions" in US 7,208,485 B2 would directly motivate a PHOSITA to apply this known anti-inflammatory therapy to hepatitis. The shared inventorship further underscores the apparent nature of this application.
• Claims Rendered Obvious: This combination would render obvious the broad method claims of the '163 patent, including Claim 1, relating to using CO to treat hepatitis.

Obviousness Considerations for Specific Claim Types:

• Claims related to specific causes of hepatitis (e.g., viral, alcoholic, drug-induced, autoimmune, post-surgical, Claim 15, Claim 17): Once the general principle of using CO for hepatitis (an inflammatory liver condition) is established as obvious from the prior art (e.g., US 6,297,262 B1), extending this treatment to different etiological subtypes of hepatitis would be an obvious variation. A PHOSITA understands that inflammation can arise from various causes (viruses, alcohol, drugs, autoimmune responses, surgical trauma). Applying a general anti-inflammatory therapy like CO, known to treat "cellular inflammation" or "tissue injury," to these different inflammatory scenarios would be an expected and obvious clinical application, rather than a novel invention. For example, administering CO in conjunction with a hepatotoxic drug (Claim 17) to prevent or treat associated hepatitis would be an obvious prophylactic or therapeutic extension of using CO for drug-induced liver inflammation, especially given the prior art's broad teaching on tissue injury and organ dysfunction.
• Claims related to abdominal surgery/liver transplantation (Claim 13): US 6,297,262 B1 and US 7,208,485 B2 explicitly mention treating or preventing "organ transplant rejection" and "ischemia-reperfusion injury" with CO. Liver transplantation inherently involves both ischemia-reperfusion injury and a significant risk of post-operative inflammation and hepatitis. A PHOSITA would have been highly motivated to apply CO treatment, already taught for these related conditions, to liver transplantation patients to mitigate these known risks.
• Claims related to a vessel with a label (Claim 19, Claim 20): If the underlying method of treating hepatitis with CO (or co-administering with hepatotoxic drugs) is deemed obvious, then the creation of a commercial product (a vessel containing medical-grade compressed CO gas) with a label instructing or indicating that obvious use would also be obvious. The label merely communicates a known or obvious therapeutic application.

Conclusion on Obviousness:

Based on the analysis, a significant portion of the claims of US 9,522,163, particularly those related to the core inventive concept of using carbon monoxide to treat hepatitis, appear to be obvious under 35 U.S.C. § 103. The clear teaching in US 6,297,262 B1 and US 7,208,485 B2 regarding CO's role in treating inflammatory conditions and organ injury provides strong motivation for a PHOSITA to apply this therapy to hepatitis, which is characterized by liver inflammation. Furthermore, the combination of US 6,297,262 B1 and US 6,613,793 B2 would render obvious the co-administration of CO with HO-1 modulators or its products, given the known mechanistic link between CO and HO-1. The specific causes of hepatitis, methods of administration, and labeling of CO vessels represent predictable applications or minor variations of the primary obvious therapeutic use.