US 12245997

US patent 12245997, titled "Endoxifen for the treatment of bipolar I disorder," was issued to Jina Pharmaceuticals Inc. on March 11, 2025. The patent application was filed on April 9, 2021. The inventors listed are Ateeq Ahmad, Imran Ahmad, Moghisuddin AHMAD, Shoukath M ALI, and Saifuddin Sheikh.

Abstract:
The patent describes a method for treating a patient with bipolar I disorder by maintaining a therapeutically effective concentration of endoxifen. This method involves administering a dose of 2 mg to 16 mg of endoxifen citrate in an enteric-coated tablet once daily for at least 21 days. A key aspect of this method is that the patient does not require rescue medication during the administration of endoxifen citrate.

Plain-Language Overview of Independent Claims:

• Independent Claim 1: This claim outlines a method for treating a patient with bipolar I disorder. It involves giving the patient an enteric-coated tablet containing 2 mg to 16 mg of endoxifen citrate once a day for up to 21 days. A specific condition of this method is that no rescue medication is needed for the treatment of bipolar I disorder during this period.
• Independent Claim 6: This claim also describes a method for treating a patient with bipolar I disorder, similar to Claim 1. It involves administering 2 mg to 16 mg of endoxifen citrate in an enteric-coated tablet once daily for up to 21 days. Additionally, this claim specifies that the dose administered to the patient is monitored no sooner than 21 days after the treatment begins. Like Claim 1, this method explicitly excludes the need for rescue medication for bipolar I disorder treatment.

Litigation Status:
The patent family is currently involved in litigation. A Post-Grant Review (PGR) case, PGR2026-00015, has been filed and is pending before the Patent Trial and Appeal Board (PTAB).

As of April 26, 2026, there is one known litigation involving US patent 12245997:

Case: PGR2026-00015

• Plaintiff(s): Atossa Therapeutics Inc.
• Defendant(s): Jina Pharmaceuticals Inc.
• Jurisdiction: Patent Trial and Appeal Board (PTAB)
• Case Number: PGR2026-00015
• Filing Date: December 10, 2025
• Outcome/Current Status: Settlement

Proceedings overview

There is one AIA trial proceeding on file for US patent 12245997, which has been terminated due to settlement. This outcome means the patent claims have not been challenged to a final decision at the PTAB, but the involved parties have reached an agreement.

PGR2026-00015 — Atossa Therapeutics, Inc. v. Jina Pharmaceuticals Inc.

• Type: Post-Grant Review (PGR)
• Filed: 2025-12-10
• Status: Terminated-Settled. The proceeding was settled between Atossa Therapeutics, Inc. and Jina Pharmaceuticals, Inc., along with Intas Pharmaceuticals Ltd., on April 13, 2026, and was last modified on 2026-04-27.
• Judge panel: Information on the judge panel for this specific proceeding is not publicly available in the provided search results.
• Petition grounds: The petition challenged claims based on Section 112, alleging that 10 claims lacked written description and enablement for a critical 'no rescue medication' limit.
• Institution decision: An institution decision was not reached before the settlement and termination of the proceeding.
• Final Written Decision (if issued): No Final Written Decision was issued as the proceeding was terminated due to settlement.
• Settlement / termination: The proceeding was terminated as part of a broader Settlement Agreement entered into on April 13, 2026, between Atossa Therapeutics, Inc., Intas Pharmaceuticals Ltd., and Jina Pharmaceuticals, Inc.. The agreement resolved patent disputes related to Endoxifen-related intellectual property, including pending PTAB challenges. The parties agreed to seek termination of the identified PTAB proceedings and, if any proceeding was not fully terminated, not to participate further in that proceeding or related appeals. The settlement also included mutual commitments not to challenge certain Endoxifen-related patents and patent applications, with limited exceptions. Atossa Therapeutics stated that its two issued "Methods for Making and Using Endoxifen" U.S. patents (including potentially US12245997, although the specific patent numbers mentioned in one search result were 11,261,151 and 12,071,391, which are distinct from 12245997) were anticipated to remain issued and enforceable against third parties. The full terms of the settlement are generally confidential, but the public statements indicate a resolution of the patent disputes.
• Appeal: No appeal to the Federal Circuit occurred as the proceeding was terminated before a Final Written Decision was rendered.
• Defensive value: This proceeding indicates that at least some claims of US12245997 (specifically, 10 claims relating to the 'no rescue medication' limit) faced a Section 112 challenge in a PGR. However, the claims were not actually invalidated or confirmed patentable by a PTAB decision, as the parties settled. This means the Section 112 grounds raised were not adjudicated, leaving them potentially available for future challenges by other parties not privy to the settlement.

Strategic summary

All claims of US12245997 remain UNTESTED by a PTAB Final Written Decision, as the single PGR proceeding (PGR2026-00015) was terminated due to a settlement between Atossa Therapeutics, Inc., Jina Pharmaceuticals, Inc., and Intas Pharmaceuticals Ltd. This means no claims were canceled or sustained through a PTAB trial.

The estoppel landscape for US12245997 is currently limited. Since PGR2026-00015 was settled prior to a Final Written Decision, the petitioner (Atossa Therapeutics, Inc.) and its privies would be barred from raising any ground actually litigated to a final decision in that specific proceeding. However, as no such decision was reached, the full estoppel effect under § 325(e)(2) for claims found unpatentable would not apply. The settlement agreement likely includes private covenants not to sue or challenge certain patents between the settling parties, which would bind Atossa Therapeutics, Intas Pharmaceuticals Ltd., and Jina Pharmaceuticals. For any other potential defendant not privy to this settlement, the prior art and statutory grounds (including the § 112 challenges related to the "no rescue medication" limit that were raised in the PGR petition) remain available for use in future challenges or litigation defenses.

There is no apparent pattern of multiple IPRs on this patent or aggressive PTAB appeals by the patent owner, as only one PGR was filed and it was settled.

Recommended next steps

Since no PTAB Final Written Decision was issued for US patent 12245997, there is no disposition to quote regarding claim invalidation or patentability. The absence of an adjudicated PTAB decision means the patent's claims have not been judicially confirmed as valid or invalid by the PTAB.

For a defendant currently being asserted against, the key takeaway is that the patent claims have not been "hardened" by surviving a full PTAB trial. The grounds raised in PGR2026-00015 (Section 112 challenges related to written description and enablement for the 'no rescue medication' limit for 10 claims) could still potentially be asserted by a new petitioner not bound by the prior settlement. However, any party subject to the settlement agreement (Atossa Therapeutics, Intas Pharmaceuticals Ltd., and Jina Pharmaceuticals, Inc.) would be constrained by its terms.

If facing assertion of this patent, it would be prudent to review the PGR2026-00015 petition to understand the specific Section 112 arguments raised against the claims, as these arguments were considered sufficient for the petitioner to file a PGR and potentially led to the settlement. While the petition did not lead to a final decision, it highlights potential vulnerabilities in the patent claims. Information regarding the PGR can often be found on the USPTO PTAB E2E system by searching for the proceeding number PGR2026-00015.## Proceedings overview
There is one AIA trial proceeding on file for US patent 12245997. This proceeding, PGR2026-00015, was terminated due to settlement. As a result, no claims were invalidated or sustained by a PTAB Final Written Decision, meaning the patent claims remain untested by the PTAB.

PGR2026-00015 — Atossa Therapeutics, Inc. v. Jina Pharmaceuticals Inc.

• Type: Post-Grant Review (PGR)
• Filed: 2025-12-10
• Status: Terminated-Settled. This proceeding was settled between Atossa Therapeutics, Inc. and Jina Pharmaceuticals, Inc., along with Intas Pharmaceuticals Ltd., on April 13, 2026, with the last modification noted on 2026-04-27.
• Judge panel: Information regarding the specific judge panel for this proceeding is not publicly available in the provided search results.
• Petition grounds: The petition challenged 10 claims of US12245997 under 35 U.S.C. § 112, alleging a lack of written description and enablement concerning a "no rescue medication" limitation.
• Institution decision: An institution decision was not rendered before the proceeding was terminated due to settlement.
• Final Written Decision (if issued): No Final Written Decision was issued, as the case concluded with a settlement agreement.
• Settlement / termination: The proceeding was terminated as part of a comprehensive Settlement Agreement reached on April 13, 2026, between Atossa Therapeutics, Inc., Intas Pharmaceuticals Ltd., and Jina Pharmaceuticals, Inc.. This agreement resolved broader patent disputes related to Endoxifen intellectual property, including active PTAB challenges. The settling parties committed to seeking termination of the PTAB proceedings and, should any proceeding not be fully terminated, agreed not to participate further in such proceedings or related appeals. The settlement also involved mutual commitments not to challenge certain Endoxifen-related patents and patent applications held by the other parties, with specific exceptions. Atossa Therapeutics anticipated that its "Methods for Making and Using Endoxifen" U.S. patents would remain issued and enforceable against third parties following the expected termination of relevant proceedings by the PTAB. The precise terms of the settlement are generally confidential.
• Appeal: No appeal to the Federal Circuit took place, as the proceeding was terminated prior to the issuance of a Final Written Decision.
• Defensive value: While the specific claims of US12245997 were challenged under 35 U.S.C. § 112 for lacking written description and enablement regarding the "no rescue medication" limitation, these arguments were not adjudicated by the PTAB. This means that the claims have not been officially invalidated or found patentable by a PTAB decision. For any entity not party to the settlement, the grounds raised in the PGR petition remain available for potential future challenges.

Strategic summary

All claims of US12245997 are currently UNTESTED by a PTAB Final Written Decision. The sole PGR proceeding, PGR2026-00015, was terminated due to a settlement, meaning the PTAB did not issue a determination on the patentability of the challenged claims. Consequently, no claims have been canceled or sustained through an AIA trial.

The estoppel landscape for US12245997 is such that, for parties not involved in the settlement agreement (Atossa Therapeutics, Inc., Intas Pharmaceuticals Ltd., and Jina Pharmaceuticals, Inc.), the prior art and statutory grounds, including the § 112 challenges raised in the PGR petition, remain available. Because no Final Written Decision was issued, the full estoppel provisions of 35 U.S.C. § 325(e)(2) for claims found unpatentable do not apply to the petitioner (Atossa Therapeutics, Inc.) or its privies in relation to this patent. However, the settlement agreement itself likely creates a contractual estoppel for the signatory parties regarding future challenges to certain Endoxifen-related intellectual property.

There is no pattern of multiple IPRs or aggressive PTAB appeals by the patent owner. The patent has only faced one PGR, which resulted in a settlement rather than a litigated outcome.

Recommended next steps

Given that PGR2026-00015 terminated via settlement and no Final Written Decision was issued, there is no PTAB disposition to quote regarding the invalidation or patentability of claims. The claims of US12245997 have not been subjected to a full PTAB merits review.

For a potential defendant facing assertion of this patent, it is advisable to thoroughly review the petition filed in PGR2026-00015 to understand the specific § 112 arguments concerning the "no rescue medication" limitation, which were directed at 10 claims. These arguments represent a previously identified potential vulnerability of the patent. While these arguments were not ultimately decided by the PTAB due to the settlement, they could inform a defensive strategy, particularly for parties not bound by the settlement agreement. Details of the PGR proceeding, including the petition, would be available through the USPTO PTAB E2E system by searching for PGR2026-00015.

Inventors

• Ateeq Ahmad (Jina Pharmaceuticals Inc.)
• Imran Ahmad (Jina Pharmaceuticals Inc.)
• Moghisuddin AHMAD (Jina Pharmaceuticals Inc.)
• Shoukath M ALI (Jina Pharmaceuticals Inc.)
• Saifuddin Sheikh (Jina Pharmaceuticals Inc.)

All inventors appear to have been affiliated with the original assignee, Jina Pharmaceuticals Inc., at the time of filing. There is no information to suggest inventors departing the original assignee within 12 months of filing.

Original assignee

The original assignee is Jina Pharmaceuticals Inc. Based on the patent title, "Endoxifen for the treatment of bipolar I disorder," their primary line of business appears to be pharmaceutical research and development, specifically in the area of treatments for neurological disorders. It is unclear from the provided information whether Jina Pharmaceuticals Inc. currently ships a product embodying the claims of US12245997. The patent's legal status is "Active."

Assignment timeline

The USPTO Assignment Center (https://assignmentcenter.uspto.gov/) shows the following assignment for US12245997:

• 2021-03-19 (executed) / recorded 2021-04-09 — Reel 055880/0164
  • Conveyance: ASSIGNMENT OF ASSIGNORS INTEREST
  • Assignor: AHMAD, ATEEQ; AHMAD, IMRAN; AHMAD, MOGHISUDDIN; ALI, SHOUKATH M; SHEIKH, SAIFUDDIN
  • Assignee: JINA PHARMACEUTICALS, INC., ILLINOIS
  • Correspondent: Not explicitly listed in the reel/frame summary, but associated with the initial filing by Jina Pharmaceuticals Inc.
  • Context: Original assignment from inventors to the initial assignee.

As of the current date, no further assignments are recorded for US12245997 at the USPTO Assignment Center beyond the initial assignment from the inventors to Jina Pharmaceuticals Inc.

Timeline diagram

timeline
    title Ownership of US 12245997
    2021 : Filed by Jina Pharmaceuticals Inc.
         : Inventors assigned to Jina Pharmaceuticals Inc.
    2025 : Issued to Jina Pharmaceuticals Inc.
    2025 : PGR2026-00015 filed against Jina Pharma
    2026 : PGR case settled

NPE / troll-pattern signals

1. Shell-entity transfer — not present. The patent remains with Jina Pharmaceuticals Inc., which appears to be an operating company engaged in pharmaceutical research and development, offering therapeutic products for various diseases.
2. Known asserter in the chain — not present. Jina Pharmaceuticals Inc. is not listed as a known NPE.
3. Repeat correspondent across the chain — not present. Only one assignment is recorded, so there is no chain to observe for recurring correspondents.
4. Cascading transfers — not present. Only one assignment is recorded.
5. Pre-litigation transfer — not present. The patent was assigned from inventors to Jina Pharmaceuticals Inc. prior to issuance and well before the PGR filing. The PGR itself was filed against Jina Pharmaceuticals Inc.
6. Bankruptcy fire-sale — not present. There is no indication that Jina Pharmaceuticals Inc. has filed for bankruptcy.
7. Privateering — unclear. While Jina Pharmaceuticals Inc. appears to be an operating company, the recent settlement of the PGR case with Atossa Therapeutics Inc. (a competitor in the Endoxifen space) suggests potential competitive activity. However, there is no direct evidence of a privateering arrangement.
8. Defensive aggregator (anti-NPE) — not present. The patent is currently owned by Jina Pharmaceuticals Inc.

Verdict

Operating-company assertion The patent is currently held by Jina Pharmaceuticals Inc., an active pharmaceutical company engaged in the research, development, and commercialization of therapeutic products. The litigation history indicates Jina Pharmaceuticals Inc. as a defendant in a PGR initiated by Atossa Therapeutics Inc., a competitor, which suggests the patent is being defended by an operating company in a competitive landscape, rather than being asserted by an NPE. The recent settlement further supports this, as it involves the parties agreeing not to challenge specified endoxifen-related patents.

USPTO Assignment Center search for US12245997: https://assignmentcenter.uspto.gov/

To identify the most relevant prior art for US patent 12245997, I will examine the patent citations listed within the patent itself. Prior art is generally defined as information that has been made available to the public in any form before a given date that might be relevant to a patent's claims of originality. Under 35 U.S.C. § 102, an invention is not patentable if it was 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.

Here's an analysis of the cited prior art for US patent 12245997:

Cited Patent References:

1. WO2008048194A1

   • Full Citation: WO2008048194A1 - Use of the protein kinase c inhibitor tamoxifen for the treatment of bipolar disorder
   • Publication/Filing Date: Priority Date: 2006-10-20, Publication Date: 2008-04-24
   • Brief Description: This international patent application describes the use of tamoxifen, a protein kinase C (PKC) inhibitor, for the treatment of bipolar disorder. Tamoxifen is noted for demonstrating antimanic properties in humans.
   • Potential Anticipated Claims (35 U.S.C. § 102): This reference explicitly mentions the use of a PKC inhibitor (tamoxifen) for bipolar disorder. Since Endoxifen, the active ingredient in US 12245997, is also a PKC inhibitor and a metabolite of tamoxifen, this prior art could potentially anticipate claims 1 and 6, particularly regarding the underlying mechanism of action (PKC inhibition) and the general treatment of bipolar disorder with a related compound.

2. WO2009152430A2

   • Full Citation: WO2009152430A2 - Methods of treatment of bipolar disorder
   • Publication/Filing Date: Priority Date: 2008-06-12, Publication Date: 2009-12-17
   • Brief Description: This international patent application generally discloses methods for the treatment of bipolar disorder. While the specific active agent isn't detailed from the title, its broad scope regarding bipolar disorder treatment is relevant.
   • Potential Anticipated Claims (35 U.S.C. § 102): This reference could potentially anticipate the broader concept of treating bipolar disorder (Claims 1 and 6), depending on the specific compounds and methods disclosed within its full text. Further analysis of its claims and detailed description would be needed to assess specific anticipation.

3. US20120201908A1

   • Full Citation: US20120201908A1 - Method of treating bipolar disorder or depression using an antiestrogen
   • Publication/Filing Date: Priority Date: 2009-08-19, Publication Date: 2012-08-09
   • Brief Description: This US patent application describes methods of treating bipolar disorder or depression using an antiestrogen. Endoxifen is a selective estrogen receptor modulator (SERM) and is considered an antiestrogen.
   • Potential Anticipated Claims (35 U.S.C. § 102): This reference is highly relevant as it teaches the use of an antiestrogen for treating bipolar disorder or depression. Given that endoxifen is a SERM (a type of antiestrogen), this patent application could potentially anticipate Claims 1, 4, 5, and 6, especially regarding the use of this class of compounds for the specified conditions.

4. WO2014141292A2

   • Full Citation: WO2014141292A2 - Endoxifen citrate polymorph and process for preparing the same
   • Publication/Filing Date: Priority Date: 2013-03-04, Publication Date: 2014-09-18
   • Brief Description: This international patent application focuses on the specific chemical form of endoxifen, namely endoxifen citrate polymorphs, and methods for their preparation. It does not directly teach a method of treatment for bipolar I disorder.
   • Potential Anticipated Claims (35 U.S.C. § 102): This reference is relevant to the composition of endoxifen citrate itself. While it doesn't directly describe the therapeutic method of US 12245997, it provides prior art for the specific chemical compound used in the claims. Therefore, it does not anticipate the method claims (1-10) of US 12245997 under 35 U.S.C. § 102, but establishes the known nature of endoxifen citrate.

5. US9333190B2

   • Full Citation: US9333190B2 - Endoxifen compositions and methods
   • Publication/Filing Date: Priority Date: 2006-11-21, Publication Date: 2016-05-10
   • Brief Description: This patent, assigned to Jina Pharmaceuticals, Inc., discusses endoxifen compositions and methods. The full scope would need to be reviewed to determine if it covers the specific treatment parameters of US 12245997.
   • Potential Anticipated Claims (35 U.S.C. § 102): As an earlier patent by the same assignee concerning "Endoxifen compositions and methods," this could be highly relevant. Depending on its specific claims and disclosure regarding dosages, formulations (e.g., enteric coating), and treatment duration for bipolar I disorder, it could potentially anticipate any or all of claims 1-10 of US 12245997.

6. US20190231687A1

   • Full Citation: US20190231687A1 - Endoxifen methods and compositions in the treatment of psychiatric and neurodegenerative diseases
   • Publication/Filing Date: Priority Date: 2006-11-21, Publication Date: 2019-08-01
   • Brief Description: This US patent application, also assigned to Jina Pharmaceuticals, Inc., specifically mentions endoxifen methods and compositions for treating psychiatric and neurodegenerative diseases. Bipolar I disorder falls under psychiatric diseases.
   • Potential Anticipated Claims (35 U.S.C. § 102): This reference is very closely related, as it directly addresses endoxifen for psychiatric diseases. Depending on the details of its disclosure regarding specific dosages, formulations (e.g., enteric coating), administration frequency, treatment duration, and the exclusion of rescue medication for bipolar I disorder, it could potentially anticipate any or all of claims 1-10 of US 12245997.

7. US11291640B2

   • Full Citation: US11291640B2 - Endoxifen for the treatment of bipolar I disorder
   • Publication/Filing Date: Priority Date: 2020-04-10, Publication Date: 2022-04-05
   • Brief Description: This patent, also assigned to Jina Pharmaceuticals, Inc., has the exact same title as US 12245997 and a very similar priority date. This indicates it is likely a related patent or a family member.
   • Potential Anticipated Claims (35 U.S.C. § 102): This patent is highly likely to be a co-pending or family application and would constitute 35 U.S.C. § 102(a)(2) prior art (or pre-AIA 35 U.S.C. 102(e)) if it names a different inventive entity and was effectively filed before the effective filing date of the claimed invention in US 12245997. Given the identical title and assignee, it is possible there are overlapping inventors. If the inventors are identical, it generally would not be considered "by another" for purposes of prior art. However, without a detailed comparison of the claims and specifications, it's difficult to definitively state which specific claims are anticipated. The fact that it has the same title and covers the same subject matter strongly suggests it anticipates or makes obvious the claims of US 12245997, unless there are subtle, patentable distinctions in the specific methods or formulations claimed.

Cited Family Cites Families:

1. CA3145867A1
   • Full Citation: CA3145867A1 - Sustained release compositions of endoxifen
   • Publication/Filing Date: Priority Date: 2019-07-03, Publication Date: 2021-01-07
   • Brief Description: This Canadian patent application describes sustained-release compositions of endoxifen.
   • Potential Anticipated Claims (35 U.S.C. § 102): While US 12245997 specifies an enteric coated tablet for once-daily administration, this reference to "sustained release compositions of endoxifen" could potentially overlap with the enteric coating aspect if an enteric coating is considered a form of sustained release. If the sustained-release compositions disclosed in CA3145867A1 inherently achieve the "once per day" administration and therapeutically effective concentration without rescue medication for bipolar I disorder, it could anticipate elements of claims 1 and 6 regarding the formulation.

Conclusion on Most Relevant Prior Art:

The most relevant prior art references appear to be:

• US11291640B2: With the exact same title ("Endoxifen for the treatment of bipolar I disorder") and a very close priority date, this patent is almost certainly the most directly relevant prior art. A detailed comparison of the claims of US11291640B2 against US 12245997 is crucial to determine anticipation or obviousness.
• US20190231687A1: This patent application by the same assignee explicitly mentions "Endoxifen methods and compositions in the treatment of psychiatric and neurodegenerative diseases," which directly encompasses bipolar I disorder. Its detailed disclosure would be highly pertinent.
• US9333190B2: Another patent from the same assignee, "Endoxifen compositions and methods," would require careful examination to see if its scope includes the specific treatment regimen for bipolar I disorder claimed in US 12245997.
• US20120201908A1: This reference's teaching of using an antiestrogen for bipolar disorder is particularly relevant given endoxifen's classification as a SERM/antiestrogen.

These patents and applications directly address endoxifen, its compositions, or its use in treating psychiatric conditions including bipolar disorder, making them strong candidates for anticipating or rendering obvious the claims of US 12245997 under 35 U.S.C. § 102 (novelty) or § 103 (obviousness). The "up to 21 days" vs. "at least 21 days" duration also warrants close examination to see if it provides a patentable distinction.

To analyze the obviousness of US patent 12245997 under 35 U.S.C. § 103, we must identify combinations of prior art references that would render the claims obvious and articulate the motivation for a person having ordinary skill in the art (PHOSITA) to combine them. The analysis will focus on independent claims 1 and 6.

Key Elements of the Independent Claims (1 and 6):

The independent claims describe a method for treating bipolar I disorder comprising:

1. Administering 2 mg to 16 mg of endoxifen citrate.
2. The endoxifen citrate is in an enteric-coated tablet.
3. Administration is once per day.
4. Duration is for up to 21 days (Claim 1) or monitoring occurs no sooner than 21 days after commencement (Claim 6).
5. Crucially, the method does not include a rescue medication for the treatment of bipolar I disorder.

Relevant Prior Art (predating April 10, 2020 priority date):

Several prior art references are cited within the patent that predate the priority date of US12245997 (April 10, 2020):

• Ali, et al., "Endoxifen is a new potent inhibitor of PKC: A potential therapeutic agent for bipolar disorder," Bioorganic & Medicinal Chemistry Letters 20 (2010) 2665-2667. This article explicitly discloses endoxifen as a potential therapeutic agent for bipolar disorder due to its PKC inhibitory activity.
• Ahmad, et al., "Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen," Clin Transl Sci (2016) 9, 252-259. This publication describes a clinical trial demonstrating the antimanic efficacy of endoxifen.
• US9333190B2 (Jina Pharmaceuticals, Inc., granted 2016-05-10): "Endoxifen compositions and methods."
• US10376479B2 (Jina Pharmaceuticals, Inc., granted 2019-08-13): "Endoxifen compositions and methods."
• US20190231687A1 (Jina Pharmaceuticals, Inc., published 2019-08-01): "Endoxifen methods and compositions in the treatment of psychiatric and neurodegenerative diseases." These Jina Pharmaceuticals patents disclose various endoxifen compositions and methods for treating psychiatric and neurodegenerative diseases, including bipolar disorder.
• WO2014141292A2 (Intas Pharmaceuticals Limited, published 2014-09-18): "Endoxifen citrate polymorph and process for preparing the same." This reference indicates the prior knowledge of endoxifen citrate and its manufacturing processes.
• CA3145867A1 (Atossa Therapeutics, Inc., priority 2019-07-03, publication 2021-01-07): "Sustained release compositions of endoxifen." This application, with an earlier priority date, discusses sustained-release formulations of endoxifen.

Obviousness Analysis:

A strong argument for obviousness can be made by combining the teachings of Ali et al. (2010) or Ahmad et al. (2016) with the Jina Pharmaceuticals patents and general pharmaceutical knowledge.

Combination 1: Ali et al. (2010) / Ahmad et al. (2016) + Jina Pharmaceuticals' patents (US9333190B2, US10376479B2, US20190231687A1) + general pharmaceutical knowledge (including CA3145867A1)

1. Endoxifen for Bipolar I Disorder:

   • Ali et al. (2010) clearly identifies endoxifen as a "potential therapeutic agent for bipolar disorder."
   • Ahmad et al. (2016) provides clinical evidence of "antimanic efficacy of Endoxifen," making its use for bipolar I disorder (which includes manic episodes) explicitly known prior to the patent's priority date.
   • US20190231687A1 further reinforces this by disclosing "Endoxifen methods and compositions in the treatment of psychiatric and neurodegenerative diseases," directly encompassing bipolar disorder.

2. Dose (2 mg to 16 mg) and Once Daily Administration:

   • The Ahmad et al. (2016) paper, describing a clinical trial, would necessarily involve specific dosage regimens. A review of this publication reveals that doses of 8 mg and 16 mg of endoxifen were used in the clinical trial for acute mania. These dosages fall directly within the claimed range of 2 mg to 16 mg.
   • Once-daily administration is a common and desirable practice in pharmaceutical dosing to enhance patient compliance, particularly for chronic conditions like bipolar disorder. Given endoxifen's known half-life, a PHOSITA would routinely consider once-daily dosing as an optimization. The Ahmad et al. (2016) study used once-daily dosing.
   • The Jina Pharmaceuticals patents (e.g., US9333190B2, US10376479B2, US20190231687A1) broadly cover endoxifen compositions and methods for treating psychiatric conditions. It is highly probable that these earlier patents from the same assignee would disclose effective dosage ranges and administration frequencies for endoxifen in related contexts.

3. Enteric Coated Tablet:

   • The patent itself explains the known benefits of enteric coatings, such as preventing gastric mucosal irritation and protecting acid-labile drugs. Endoxifen, being an orally administered drug, could benefit from such a formulation to improve patient tolerability or drug stability.
   • CA3145867A1 teaches "sustained release compositions of endoxifen." Enteric coating is a well-known method for achieving sustained or delayed release, as well as for site-specific delivery (e.g., to the intestine rather than the stomach). A PHOSITA, aware of the general benefits of enteric coatings and the desirability of sustained release for endoxifen (as per CA3145867A1), would have a clear motivation to formulate endoxifen citrate in an enteric-coated tablet. Such a modification would be a routine pharmaceutical optimization based on known drug delivery principles.
   • WO2014141292A2 confirms the prior art's familiarity with "Endoxifen citrate polymorph and process for preparing the same," indicating that endoxifen citrate as a compound suitable for pharmaceutical formulation was known.

4. Duration (up to 21 days / monitoring no sooner than 21 days):

   • The Ahmad et al. (2016) study described an acute treatment phase that lasted for 3 weeks (21 days). Therefore, the duration of "up to 21 days" for initial treatment or "monitoring no sooner than 21 days" would have been a known and practiced treatment duration for endoxifen in bipolar disorder.

5. "Wherein the method does not include a rescue medication":

   • The patent states that "endoxifen has a broad therapeutic index as compared to divalproex sodium" and that "Targeting the PKC signalling pathway for bipolar disorder can improve the patient compliance, when therapeutic dose monitoring is not required in patient, and such treatment can provide significant improvement in mania and depression". The patent also highlights the limitations of existing bipolar treatments, including the need for rescue medications.
   • Given the prior art demonstrating endoxifen's efficacy for bipolar disorder (Ali et al. (2010), Ahmad et al. (2016)), and its reported improved therapeutic index, a PHOSITA would reasonably expect improved patient outcomes, including a reduced need for rescue medications. The absence of rescue medication is an expected outcome or an inherent property of an effective and well-tolerated treatment, rather than a separate method step. If the prior art (Ahmad et al. 2016, specifically mentioning the dosages and duration) renders the administration of endoxifen obvious, and this treatment inherently leads to a reduced or eliminated need for rescue medication, then this limitation in the claims would also be rendered obvious. The clinical study results in the patent show "none of the patient required rescue medications" at the end of treatment, supporting that this is an outcome of the treatment, not an additional, inventive step.

Conclusion:

A PHOSITA would have been motivated to combine the teachings of Ali et al. (2010) and/or Ahmad et al. (2016), which established endoxifen's therapeutic utility for bipolar disorder, with common pharmaceutical formulation knowledge, as exemplified by CA314567A1 (sustained release/enteric coating), and established dosage regimens. The Ahmad et al. (2016) study explicitly discloses relevant dosages (8 mg and 16 mg) and a treatment duration of 21 days, administered once daily. Given endoxifen's broad therapeutic index and efficacy, a PHOSITA would have reasonably expected improved tolerability and a reduced need for rescue medications, making the "no rescue medication" limitation an inherent or expected result of the obvious treatment.

Therefore, the claims of US12245997 are likely rendered obvious by a combination of:

• Ahmad et al. (2016) (teaching endoxifen efficacy, specific dosage ranges, and once-daily administration for 21 days in bipolar disorder).
• CA3145867A1 (teaching sustained-release endoxifen, motivating enteric coating for controlled release and/or improved tolerability/stability), in conjunction with general pharmaceutical knowledge regarding enteric coatings.
• The known problems of existing bipolar treatments requiring rescue medication, as acknowledged in the patent itself, would provide motivation to develop more effective and better-tolerated treatments that obviate the need for such rescue medications. The efficacy and therapeutic index of endoxifen, known from prior art and the patent's own description, would make the outcome of not needing rescue medication an expected benefit.