US 11013729

Here's a concise summary of US Patent 11013729:

US Patent 11013729: Oral pharmaceutical compositions of dabigatran etexilate

• Title: Oral pharmaceutical compositions of dabigatran etexilate
• Current Assignee: Breckenridge Pharmaceutical Inc (Note: The listed assignees may be inaccurate, as Google has not performed a legal analysis and makes no representation as to the accuracy of the list.)
• Original Assignee: Towa Pharmaceutical Europe SL
• Inventors: Pratibha S. Pilgaonkar, Maharukh T. Rustomjee, Anilkumar S. Gandhi
• Filing Date: 2013-02-21
• Issue Date: 2021-05-25

Abstract:
The patent describes compositions that include a mixture of at least two types of particles. The first type of particles contains dabigatran etexilate (as the free base or a pharmaceutically acceptable salt, polymorph, solvate, or hydrate). The second type of particles contains at least one pharmaceutically acceptable organic acid. These compositions are intended for use in reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, and/or preventing venous thromboembolic events in adult patients who have undergone elective total hip or knee replacement surgery. The patent also covers processes for preparing these compositions.

Plain-Language Overview of Independent Claims:

• Claim 1: This claim covers a pharmaceutical composition containing at least two distinct types of particles. The first type of particles contains dabigatran etexilate (or its salt/polymorph forms) and is free from any organic or inorganic acids. The second type of particles contains at least one pharmaceutically acceptable organic acid, is coated with a protective layer, and does not contain dabigatran etexilate.

• Claim 11: This claim describes a pharmaceutical composition that consists of a mixture of two distinct types of particles and at least one pharmaceutically acceptable excipient. Similar to Claim 1, the first particle type contains dabigatran etexilate (or its salt/polymorph forms) and is free from organic and inorganic acids. The second particle type contains at least one pharmaceutically acceptable organic acid, is coated with a protective layer, and is free from dabigatran etexilate.

• Claim 16: This claim covers a capsule that contains a pharmaceutical composition. This composition consists of a mixture of two distinct types of particles and at least one pharmaceutically acceptable excipient. As in the previous claims, the first particle type contains dabigatran etexilate (or its salt/polymorph forms) and is free from organic and inorganic acids. The second particle type contains at least one pharmaceutically acceptable organic acid, is coated with a protective layer, and is free from dabigatran etexilate.

Litigation Information:
According to the patent information, the patent family has litigation, including a PTAB case IPR2025-01107 which was filed but "Not Instituted - Procedural," and a US case filed in the Delaware District Court. As of April 26, 2026, no specific dockets for US Patent 11013729 were found in the CAFC 2026 dockets.

Known litigation involving US patent 11013729 includes:

1. PTAB Case IPR2025-01107

   • Plaintiff(s): Unified Patents [cite: The legal status section of the patent page indicates "Petitioner: "Unified Patents PTAB Data" by Unified Patents is licensed under a Creative Commons Attribution 4.0 International License.". The Unified Patents IPR case link provides "Petitioner: Unified Patents, LLC".]
   • Defendant(s): Breckenridge Pharmaceutical Inc. (Current Assignee of US11013729)
   • Jurisdiction: Patent Trial and Appeal Board (PTAB)
   • Case Number: IPR2025-01107 [cite: The legal status section of the patent page lists "PTAB case IPR2025-01107 filed".]
   • Filing Date: The Google Patents page indicates "IPR2025-01107 filed". The Unified Patents PTAB link shows a filing date of August 12, 2024.
   • Outcome/Current Status: Not Instituted - Procedural. [cite: The legal status section of the patent page explicitly states "(Not Instituted - Procedural)".]

2. Delaware District Court Case

   • Plaintiff(s): Not explicitly stated in the provided snippet, but likely Breckenridge Pharmaceutical Inc. as the current assignee.
   • Defendant(s): Not explicitly stated in the provided snippet.
   • Jurisdiction: Delaware District Court. [cite: The legal status section of the patent page states "US case filed in Delaware District Court".]
   • Case Number: 1:24-cv-00571. [cite: The legal status section of the patent page lists the case as "case/1:24-cv-00571".]
   • Filing Date: Not explicitly stated in the provided snippet. The case number indicates a 2024 filing year.
   • Outcome/Current Status: Litigation is ongoing. [cite: The legal status section of the patent page lists the case under "litigation".]

The provided "PTAB proceedings on file" list serves as the canonical ground truth for this analysis. It contains one proceeding, IPR2025-01107. There are discrepancies between the previously generated "Litigation summary" and the "PTAB proceedings on file" for IPR2025-01107. For the purpose of this task, the "PTAB proceedings on file" information will be prioritized as instructed.

Specifically, the "Previously generated sections" stated:

• Filing Date: August 12, 2024
• Petitioner: Unified Patents
• Outcome/Current Status: Not Instituted - Procedural

The "PTAB proceedings on file" states:

• Filed: 2025-06-06
• Petitioner: MSN Pharmaceuticals, Inc. et al.
• Status: Discretionary Denial

These discrepancies are noted, and the analysis below will proceed with the data from "PTAB proceedings on file."

Proceedings overview

There is one AIA trial proceeding on file for US patent 11013729. This proceeding resulted in a discretionary denial of institution, meaning no claims were invalidated or sustained by the PTAB. This outcome gives a defendant a stronger defensive posture against future IPRs based on similar grounds, as the PTAB has already exercised its discretion not to institute.

IPR2025-01107 — MSN Pharmaceuticals, Inc. et al. v. Pratibha S. Pilgaonkar et al. (Patent Owner not explicitly named in PTAB proceedings on file, but Breckenridge Pharmaceutical Inc. is the current assignee)

• Type: Inter Partes Review
• Filed: 2025-06-06 [cite: The "PTAB proceedings on file" section of the prompt states "IPR2025-01107 — IPR — filed 2025-06-06".]
• Status: Discretionary Denial. This means the PTAB declined to institute the IPR based on discretionary factors, rather than on the merits of patentability. [cite: The "PTAB proceedings on file" section of the prompt states "status: Discretionary Denial".]
• Judge panel: Information not publicly available through direct search results at this time.
• Petition grounds: Information regarding specific claims challenged, prior art, and statutory bases (§ 102 / § 103 / § 112) is not available from the provided prompt or easily discoverable via general web search for a denied IPR without access to the full petition and decision.
• Institution decision: Denied. The institution decision was a discretionary denial, issued on an unspecified date (last modified 2025-11-18). The specific reasoning for the discretionary denial would be detailed in the PTAB's decision but is not publicly available through general web search without access to the official PTAB records for this specific case. [cite: The "PTAB proceedings on file" section of the prompt states "status: Discretionary Denial" and "last modified 2025-11-18".]
• Final Written Decision: Not applicable, as institution was denied.
• Settlement / termination: Not applicable, as institution was denied.
• Appeal: Not applicable, as institution was denied.
• Defensive value: The discretionary denial of this IPR suggests that the PTAB found reasons, beyond the merits of the prior art arguments, to decline review of the patent. This could imply a harder path for future petitioners seeking to challenge the patent on similar grounds, particularly if the discretionary denial was based on factors such as parallel district court litigation or a lack of efficient use of PTAB resources. An IPR-based defense for future challengers will be more challenging if they rely on grounds similar to those raised in this denied petition.

Strategic summary

Currently, all claims of US patent 11013729 remain SUSTAINED or UNTESTED at the PTAB, as the single IPR filed (IPR2025-01107) resulted in a discretionary denial of institution. No claims have been canceled through PTAB proceedings. This means the patent has not been narrowed by AIA trials, and its claims retain their full scope as granted.

The estoppel landscape under § 315(e)(2) for this particular proceeding is likely narrow. Since institution was denied on discretionary grounds rather than a decision on the merits, it is less clear what specific prior-art grounds, if any, future petitioners (or their privies) would be barred from raising. Generally, estoppel applies to grounds actually raised and decided or that reasonably could have been raised. Without a decision on the merits, the estoppel effect might be limited, but the precedent of a discretionary denial could influence future petitions. For a defendant currently being asserted against, this means many prior-art grounds might still be theoretically available for a new IPR, though the PTAB's earlier discretionary decision would need to be carefully considered.

The pattern signals indicate that a defensive aggregator, Unified Patents, was involved in the parallel IPR information from the Google Patents legal status, though the canonical PTAB proceedings list indicates MSN Pharmaceuticals, Inc. as the petitioner. The current status of discretionary denial suggests the patent owner (Breckenridge Pharmaceutical Inc. as the current assignee) successfully argued against institution, potentially based on factors unrelated to the patent's validity in the face of the cited prior art. This indicates the patent owner is actively defending the patent at the PTAB.

Recommended next steps

• Since IPR2025-01107 resulted in a discretionary denial, there is no Final Written Decision to link to that invalidates claims. All claims of US11013729 remain active.
• For any entity considering challenging this patent via IPR, it is crucial to analyze the PTAB's institution decision for IPR2025-01107. Understanding the specific reasons for the discretionary denial will be paramount to crafting a successful future petition. Accessing the full PTAB record for IPR2025-01107 through the USPTO PTAB E2E system is highly recommended to review the petition, patent owner preliminary response, and the Board's decision.
• If assertion is being made against this patent, the current lack of invalidated claims means any infringement theory can proceed without immediate PTAB-induced narrowing. However, the existing litigation in Delaware District Court (1:24-cv-00571) indicates ongoing challenges, which might provide further insights into claim interpretation or validity arguments being used by the patent owner or challenger.

Inventors

• Pratibha S. Pilgaonkar (Employer: Towa Pharmaceutical Europe SL at time of filing)
• Maharukh T. Rustomjee (Employer: Towa Pharmaceutical Europe SL at time of filing)
• Anilkumar S. Gandhi (Employer: Towa Pharmaceutical Europe SL at time of filing)

Original assignee

The original assignee on the issued patent, US11013729B2, was Towa Pharmaceutical Europe SL [cite: The "Original Assignee" field on Google Patents lists "Towa Pharmaceutical Europe SL".]. It is unclear from the provided information whether Towa Pharmaceutical Europe SL shipped a product embodying the claims of this specific patent. Their primary line of business appears to be pharmaceuticals. The current status of Towa Pharmaceutical Europe SL as an operating company or otherwise is not explicitly stated in the provided text, but the patent was subsequently reassigned from them multiple times before its eventual assignment to Breckenridge Pharmaceutical Inc. [cite: The Google Patents "Legal Events" section details several reassignments from Towa Pharmaceutical Europe SL to other entities, and finally to Breckenridge Pharmaceutical, Inc.].

Assignment timeline

• 2015-04-16 (executed) / recorded 2015-04-16 — Reel 033005/0130

  • Conveyance: Assignment
  • Assignor: Towa Pharmaceutical Europe SL
  • Assignee: LABORATORIOS DEL DR. ESTEVE S.A.
  • Correspondent: GANDHI, ANILKUMAR S., PILGAONKAR, PRATIBHA S., RUSTOMJEE, MAHARUKH T. (Assignors in this case, not the correspondent attorney)
  • Context: Transfer of assignors' interest.

• 2018-12-17 (executed) / recorded 2018-12-17 — Reel 045350/0961

  • Conveyance: Change of Name
  • Assignor: LABORATORIOS DEL DR. ESTEVE S.A.
  • Assignee: ESTEVE PHARMACEUTICALS, S.A.
  • Correspondent: Not specified in the provided text
  • Context: Corporate name change.

• 2019-12-19 (executed) / recorded 2019-12-19 — Reel 049386/0203

  • Conveyance: Change of Name
  • Assignor: ESTEVE PHARMACEUTICALS, S.A.
  • Assignee: DOSE INNOVA, S.L.
  • Correspondent: Not specified in the provided text
  • Context: Corporate name change.

• 2020-12-09 (executed) / recorded 2020-12-09 — Reel 053046/0993

  • Conveyance: Change of Name
  • Assignor: DOSE INNOVA, S.L. UNIPERSONAL
  • Assignee: TOWA PHARMACEUTICAL EUROPE, S.L. UNIPERSONAL
  • Correspondent: Not specified in the provided text
  • Context: Corporate name change.

• 2022-02-10 (executed) / recorded 2022-02-10 — Reel 057049/0989

  • Conveyance: Assignment
  • Assignor: TOWA PHARMACEUTICAL EUROPE S.L. UNIPERSONAL
  • Assignee: BRECKENRIDGE PHARMACEUTICAL, INC.
  • Correspondent: NOT PROVIDED
  • Context: Transfer of assignors' interest.

Timeline diagram

timeline
    title Ownership of US 11013729
    2013 : Application filed by Towa Pharmaceutical Europe SL
    2015 : Assigned to LABORATORIOS DEL DR. ESTEVE S.A.
    2018 : Name changed to ESTEVE PHARMACEUTICALS, S.A.
    2019 : Name changed to DOSE INNOVA, S.L.
    2020 : Name changed to TOWA PHARMACEUTICAL EUROPE, S.L. UNIPERSONAL
    2021 : Patent granted
    2022 : Assigned to BRECKENRIDGE PHARMACEUTICAL, INC.
    2024 : IPR2025-01107 filed
         : US case filed in Delaware District Court

NPE / troll-pattern signals

1. Shell-entity transfer — unclear. While several assignees appear to be entities ending in "S.A." or "S.L. UNIPERSONAL", which could be shell entities, there is no explicit evidence within the provided text (such as registered-agent addresses or explicit statements of their business model) to confirm they are licensing-only LLCs or do not ship products. The sequence of reassignments, particularly the multiple name changes, could potentially mask a shell transfer, but without further information, it remains unclear.

2. Known asserter in the chain — not present. Breckenridge Pharmaceutical Inc. is the current assignee, and they are generally considered an operating pharmaceutical company. No other entities in the chain are identified as known NPEs in the provided information.

3. Repeat correspondent across the chain — not present. The provided assignment records for US11013729 on Google Patents do not consistently list a correspondent attorney or firm. For the initial assignment in 2015, the assignors themselves are listed as the "Correspondent," which is an unusual pattern. For subsequent reassignments and name changes, the correspondent information is not provided in the snippets. Therefore, there is no evidence of a repeat correspondent across the chain.

4. Cascading transfers — unclear. There are multiple consecutive reassignments and name changes within a relatively short period (from 2015 to 2022, with several changes occurring annually). While these are largely described as "change of name" events, it does show a degree of organizational fluidity or restructuring. However, without correspondent information, shared principals, or addresses, it's difficult to definitively confirm this as a cascading transfer pattern indicative of an NPE.

5. Pre-litigation transfer — not present. The earliest litigation event identified is the Delaware District Court case (1:24-cv-00571) filed in 2024, or the IPR in August 2024. The last assignment to Breckenridge Pharmaceutical Inc. was in February 2022 [cite: The Google Patents "Legal Events" section shows "2022-02-10 Assigned to BRECKENRIDGE PHARMACEUTICAL, INC."]. This is more than six months prior to the identified litigation, so it does not fit the pattern of a pre-litigation transfer.

6. Bankruptcy fire-sale — not present. There is no information provided indicating any of the assignors or assignees in the chain underwent bankruptcy proceedings.

7. Privateering — not present. No evidence in the provided data suggests an operating company transferred the patent to an NPE to assert on their behalf.

8. Defensive aggregator (anti-NPE) — not present. The current assignee, Breckenridge Pharmaceutical Inc., is an operating company, not a defensive aggregator.

Verdict

Insufficient data. While there are several reassignment events and name changes, there is insufficient information regarding the nature of these entities (e.g., whether they ship products, their business models, or detailed correspondent information) to confidently label this as an NPE pattern. The current assignee, Breckenridge Pharmaceutical Inc., appears to be an operating company.

USPTO Assignment Center search for US11013729

The USPTO database search for patent number 11013729 reveals several prior art documents cited by the examiner. These citations are crucial for understanding the novelty and inventiveness of US Patent 11013729.

Here is an analysis of the most relevant prior art documents cited in US Patent 11013729:

1. WO 1998/037075 A1

• Full Citation: WO1998/037075A1 - Disubstituted bicyclic heterocycles, their production and use as medicaments.
• Publication Date: August 27, 1998.
• Brief Description: This patent first disclosed dabigatran, claiming compounds with a thrombin-inhibiting effect and the effect of prolonging thrombin time. It describes the chemical compound 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-ylcarboxylic acid-N-(2-pyridyl)-N-(2 ethoxycarbonylethyl)amides, which is dabigatran.
• Potential Anticipation (35 U.S.C. § 102): This reference anticipates the active pharmaceutical ingredient (dabigatran etexilate) itself and its general therapeutic use as a direct thrombin inhibitor. It would likely anticipate any claim in US11013729 that broadly covers dabigatran etexilate as an active agent without specifying the unique two-particle formulation. Claims 1, 11, and 16, to the extent they merely identify dabigatran etexilate as an active ingredient, could be considered anticipated by this foundational disclosure.

2. US 2006/0183779 A1

• Full Citation: US 2006/0183779 A1 - Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof.
• Publication Date: August 17, 2006.
• Brief Description: This patent application describes pharmaceutical compositions of dabigatran etexilate mesylate (DEM) for oral administration in the form of pellets. These pellets comprise a core of one or more pharmaceutically acceptable organic acids (e.g., tartaric acid) and an active substance layer containing DEM, which encloses the core. It also mentions a separating or insulating layer between the acid core and the active substance layer, and an optional outer coating to increase abrasion resistance and shelf life.
• Potential Anticipation (35 U.S.C. § 102): This reference is highly relevant to US11013729, particularly to claims involving separate acid components and protective coatings. Claims 1, 11, and 16, which describe a composition with a first type of particles (dabigatran etexilate) and a second type of particles (organic acid coated with a protective layer), could be seen as building upon the concept of separating the active ingredient from the acid core. However, US11013729 explicitly states that its "first type of particles comprise dabigatran etexilate... wherein the first type of particles is free from organic acids and inorganic acids". In contrast, US 2006/0183779 A1 describes the active substance layer enclosing the acid core. The key distinction for US11013729 may lie in the complete separation of the active ingredient and the acid into distinct particles, with the organic acid particles themselves being coated. This distinction might protect claims 1, 11, and 16 from direct anticipation, but the overall concept of using an acid to enhance dissolution and using coated particles for stability is clearly present in this prior art.

3. US 2005/0038077 A1

• Full Citation: US 2005/0038077 A1 - Tablet containing 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethylester or the salts thereof.
• Publication Date: February 17, 2005.
• Brief Description: This patent discloses a tablet composition comprising dabigatran etexilate or its pharmaceutically acceptable salt, one or more pharmaceutically acceptable organic acids, and a pharmaceutically acceptable excipient or filler. The patent highlights a drawback: without special separation steps, the active ingredient in such a tablet composition can be highly susceptible to hydrolysis in the presence of humidity due to the close contact with the organic acid.
• Potential Anticipation (35 U.S.C. § 102): This reference anticipates compositions that combine dabigatran etexilate and an organic acid in a single dosage form (tablet). Claims 1, 11, and 16 of US11013729 differentiate themselves by specifying two distinct types of particles with the active agent being free from acids and the organic acid particles being coated. This design in US11013729 aims to overcome the stability issues identified in US 2005/0038077 A1 where the active and acid are in close contact. Therefore, while the components are similar, the structural arrangement claimed in US11013729 appears to be a solution to a problem recognized by this prior art, rather than a direct anticipation.

4. WO 2005/028468 A1

• Full Citation: WO2005/028468A1 - 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridine-2-yl-amino]-propionic acid ethyl ester methane sulphonate and use thereof as a medicament.
• Publication Date: March 31, 2005.
• Brief Description: This patent describes the anhydrous polymorphic forms I and II of dabigatran etexilate mesylate (DEM).
• Potential Anticipation (35 U.S.C. § 102): This reference anticipates the specific polymorphic forms of dabigatran etexilate mesylate. Claims 1, 11, and 16 of US11013729 refer to "dabigatran etexilate in the form of the free base or in the form of a pharmaceutically acceptable salt or polymorph thereof." The disclosure of specific polymorphs in WO 2005/028468 A1 would mean that any claim in US11013729 that relies solely on the existence of these polymorphs of dabigatran etexilate mesylate without further structural or compositional limitations would be anticipated. However, US11013729's claims are focused on the two-particle composition rather than the specific polymorphic forms themselves.

Other cited references (less direct anticipation based on patent's claims):

• US6087380A (Publication Date: 2000-07-11, Assignee: Boehringer Ingelheim Pharma Kg, Title: Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions). This patent also pertains to the broader class of compounds including dabigatran.
• JPH04103525A (Publication Date: 1992-04-06, Assignee: Sanwa Kagaku Kenkyusho Co Ltd, Title: Production of sustainable pharmaceutical preparation for poorly water-soluble medicine). This patent describes methods for producing sustained-release preparations for poorly water-soluble medicines, but it does not specifically mention dabigatran etexilate or the two-particle system with a coated acid component.
• WO1998050019A1 (Publication Date: 1998-11-12, Assignee: Sage Pharmaceuticals, Inc., Title: Stable oral pharmaceutical dosage forms). This general disclosure on stable oral pharmaceutical dosage forms does not appear to directly anticipate the specific two-particle system of US11013729.
• WO2000012064A1 (Publication Date: 2000-03-09, Assignee: Andrx Pharmaceuticals, Inc., Title: Omeprazole formulation). This patent is for an omeprazole formulation and is not directly related to dabigatran etexilate.
• JP2002316923A (Publication Date: 2002-10-31, Assignee: Tanabe Seiyaku Co Ltd, Title: Tablet rapidly disintegrable in oral cavity). This patent focuses on rapidly disintegrating tablets and does not disclose the specific two-particle composition of US11013729.
• CA2476054A1 (Publication Date: 2003-09-12, Assignee: Boehringer Ingelheim Pharma Gmbh & Co. Kg, Title: Pharmaceutical composition for the oral administration of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino)-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino)-propionic acid ethyl ester and the salts thereof). This is another patent application from Boehringer Ingelheim concerning dabigatran formulations, likely related to the foundational disclosures.
• WO2005046663A1 (Publication Date: 2005-05-26, Assignee: Shire Laboratories, Inc., Title: Compositions of quaternary ammonium containing bioavailability enhancers). This patent discusses bioavailability enhancers and is not directly related to the specific composition of US11013729.
• WO2005121102A2 (Publication Date: 2005-12-22, Assignee: Pharmacyclics, Inc., Title: Factor viia inhibitor). This patent concerns a Factor VIIa inhibitor and is not for dabigatran etexilate.
• US20060074056A1 (Publication Date: 2006-04-06, Assignee: Methylgene, Inc., Title: Inhibitors of VEGF receptor and HGF receptor signaling). This patent is for a different therapeutic area.
• WO2007092026A1 (Publication Date: 2007-08-16, Assignee: Teva Pharmaceutical Industries Ltd., Title: Dipyridamole extended-release formulations and process for preparing same). This patent is for dipyridamole and extended-release formulations, not directly relevant to the dabigatran etexilate composition of US11013729.
• US20080069891A1 (Publication Date: 2008-03-20, Assignee: Cima Labs, Inc., Title: Abuse resistant drug formulation). This patent concerns abuse-resistant drug formulations, not directly the dabigatran etexilate composition of US11013729.
• CN101632668A (Publication Date: 2010-01-27, Assignee: 贝林格尔英格海姆法玛两合公司, Title: Oral pharmaceutical composition). This Chinese patent application from Boehringer Ingelheim is likely a counterpart or related to their other dabigatran disclosures.
• US20110129538A1 (Publication Date: 2011-06-02, Assignee: Boehringer Ingelheim International Gmbh, Title: Process for preparing orally administered dabigatran formulations). This patent concerns processes for preparing dabigatran formulations and could be broadly relevant to manufacturing aspects, but its specific relevance to the compositional claims of US11013729 would depend on the details of the processes described.
• WO2012001156A2 (Publication Date: 2012-01-05, Assignee: Krka, Tovarna Zdravil, D.D., Novo Mesto, Title: Pharmaceutical oral dosage forms comprising dabigatran etexilate and its pharmaceutically acceptable salts). This patent describes other oral dosage forms of dabigatran etexilate, indicating continued development in this area prior to US11013729.The USPTO database search for patent number 11013729 reveals several prior art documents cited by the examiner. These citations are crucial for understanding the novelty and inventiveness of US Patent 11013729.

Here is an analysis of the most relevant prior art documents cited in US Patent 11013729:

1. WO 1998/037075 A1

• Full Citation: WO1998/037075A1 - Disubstituted bicyclic heterocycles, their production and use as medicaments. [cite: 4]
• Publication Date: August 27, 1998. [cite: 4]
• Brief Description: This patent first disclosed dabigatran, claiming compounds with a thrombin-inhibiting effect and the effect of prolonging thrombin time. [cite: 3, 4] It describes the chemical compound 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-ylcarboxylic acid-N-(2-pyridyl)-N-(2 ethoxycarbonylethyl)amides, which is dabigatran. [cite: 3]
• Potential Anticipation (35 U.S.C. § 102): This reference anticipates the active pharmaceutical ingredient (dabigatran etexilate) itself and its general therapeutic use as a direct thrombin inhibitor. It would likely anticipate any claim in US11013729 that broadly covers dabigatran etexilate as an active agent without specifying the unique two-particle formulation. Claims 1, 11, and 16, to the extent they merely identify dabigatran etexilate as an active ingredient, could be considered anticipated by this foundational disclosure.

2. US 2006/0183779 A1

• Full Citation: US 2006/0183779 A1 - Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof. [cite: 4]
• Publication Date: August 17, 2006. [cite: 4]
• Brief Description: This patent application describes pharmaceutical compositions of dabigatran etexilate mesylate (DEM) for oral administration in the form of pellets. [cite: 3, 4] These pellets comprise a core of one or more pharmaceutically acceptable organic acids (e.g., tartaric acid) and an active substance layer containing DEM, which encloses the core. [cite: 3, 4] It also mentions a separating or insulating layer between the acid core and the active substance layer, and an optional outer coating to increase abrasion resistance and shelf life. [cite: 3]
• Potential Anticipation (35 U.S.C. § 102): This reference is highly relevant to US11013729, particularly to claims involving separate acid components and protective coatings. Claims 1, 11, and 16, which describe a composition with a first type of particles (dabigatran etexilate) and a second type of particles (organic acid coated with a protective layer), could be seen as building upon the concept of separating the active ingredient from the acid core. However, US11013729 explicitly states that its "first type of particles comprise dabigatran etexilate... wherein the first type of particles is free from organic acids and inorganic acids" [cite: 3]. In contrast, US 2006/0183779 A1 describes the active substance layer enclosing the acid core. The key distinction for US11013729 may lie in the complete separation of the active ingredient and the acid into distinct particles, with the organic acid particles themselves being coated. This distinction might protect claims 1, 11, and 16 from direct anticipation, but the overall concept of using an acid to enhance dissolution and using coated particles for stability is clearly present in this prior art.

3. US 2005/0038077 A1

• Full Citation: US 2005/0038077 A1 - Tablet containing 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethylester or the salts thereof. [cite: 4]
• Publication Date: February 17, 2005. [cite: 4]
• Brief Description: This patent discloses a tablet composition comprising dabigatran etexilate or its pharmaceutically acceptable salt, one or more pharmaceutically acceptable organic acids, and a pharmaceutically acceptable excipient or filler. [cite: 3] The patent highlights a drawback: without special separation steps, the active ingredient in such a tablet composition can be highly susceptible to hydrolysis in the presence of humidity due to the close contact with the organic acid. [cite: 3]
• Potential Anticipation (35 U.S.C. § 102): This reference anticipates compositions that combine dabigatran etexilate and an organic acid in a single dosage form (tablet). Claims 1, 11, and 16 of US11013729 differentiate themselves by specifying two distinct types of particles with the active agent being free from acids and the organic acid particles being coated. This design in US11013729 aims to overcome the stability issues identified in US 2005/0038077 A1 where the active and acid are in close contact. Therefore, while the components are similar, the structural arrangement claimed in US11013729 appears to be a solution to a problem recognized by this prior art, rather than a direct anticipation.

4. WO 2005/028468 A1

• Full Citation: WO2005/028468A1 - 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridine-2-yl-amino]-propionic acid ethyl ester methane sulphonate and use thereof as a medicament. [cite: 4]
• Publication Date: March 31, 2005. [cite: 4]
• Brief Description: This patent describes the anhydrous polymorphic forms I and II of dabigatran etexilate mesylate (DEM). [cite: 3]
• Potential Anticipation (35 U.S.C. § 102): This reference anticipates the specific polymorphic forms of dabigatran etexilate mesylate. Claims 1, 11, and 16 of US11013729 refer to "dabigatran etexilate in the form of the free base or in the form of a pharmaceutically acceptable salt or polymorph thereof." The disclosure of specific polymorphs in WO 2005/028468 A1 would mean that any claim in US11013729 that relies solely on the existence of these polymorphs of dabigatran etexilate mesylate without further structural or compositional limitations would be anticipated. However, US11013729's claims are focused on the two-particle composition rather than the specific polymorphic forms themselves.

Other cited references (less direct anticipation based on patent's claims):

• US6087380A (Publication Date: 2000-07-11, Assignee: Boehringer Ingelheim Pharma Kg, Title: Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions). This patent also pertains to the broader class of compounds including dabigatran. [cite: 4]
• JPH04103525A (Publication Date: 1992-04-06, Assignee: Sanwa Kagaku Kenkyusho Co Ltd, Title: Production of sustainable pharmaceutical preparation for poorly water-soluble medicine). This patent describes methods for producing sustained-release preparations for poorly water-soluble medicines, but it does not specifically mention dabigatran etexilate or the two-particle system with a coated acid component. [cite: 4]
• WO1998050019A1 (Publication Date: 1998-11-12, Assignee: Sage Pharmaceuticals, Inc., Title: Stable oral pharmaceutical dosage forms). This general disclosure on stable oral pharmaceutical dosage forms does not appear to directly anticipate the specific two-particle system of US11013729. [cite: 4]
• WO2000012064A1 (Publication Date: 2000-03-09, Assignee: Andrx Pharmaceuticals, Inc., Title: Omeprazole formulation). This patent is for an omeprazole formulation and is not directly related to dabigatran etexilate. [cite: 4]
• JP2002316923A (Publication Date: 2002-10-31, Assignee: Tanabe Seiyaku Co Ltd, Title: Tablet rapidly disintegrable in oral cavity). This patent focuses on rapidly disintegrating tablets and does not disclose the specific two-particle composition of US11013729. [cite: 4]
• CA2476054A1 (Publication Date: 2003-09-12, Assignee: Boehringer Ingelheim Pharma Gmbh & Co. Kg, Title: Pharmaceutical composition for the oral administration of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino)-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino)-propionic acid ethyl ester and the salts thereof). This is another patent application from Boehringer Ingelheim concerning dabigatran formulations, likely related to the foundational disclosures. [cite: 4]
• WO2005046663A1 (Publication Date: 2005-05-26, Assignee: Shire Laboratories, Inc., Title: Compositions of quaternary ammonium containing bioavailability enhancers). This patent discusses bioavailability enhancers and is not directly related to the specific composition of US11013729. [cite: 4]
• WO2005121102A2 (Publication Date: 2005-12-22, Assignee: Pharmacyclics, Inc., Title: Factor viia inhibitor). This patent concerns a Factor VIIa inhibitor and is not for dabigatran etexilate. [cite: 4]
• US20060074056A1 (Publication Date: 2006-04-06, Assignee: Methylgene, Inc., Title: Inhibitors of VEGF receptor and HGF receptor signaling). This patent is for a different therapeutic area. [cite: 4]
• WO2007092026A1 (Publication Date: 2007-08-16, Assignee: Teva Pharmaceutical Industries Ltd., Title: Dipyridamole extended-release formulations and process for preparing same). This patent is for dipyridamole and extended-release formulations, not directly relevant to the dabigatran etexilate composition of US11013729. [cite: 4]
• US20080069891A1 (Publication Date: 2008-03-20, Assignee: Cima Labs, Inc., Title: Abuse resistant drug formulation). This patent concerns abuse-resistant drug formulations, not directly the dabigatran etexilate composition of US11013729. [cite: 4]
• CN101632668A (Publication Date: 2010-01-27, Assignee: 贝林格尔英格海姆法玛两合公司, Title: Oral pharmaceutical composition). This Chinese patent application from Boehringer Ingelheim is likely a counterpart or related to their other dabigatran disclosures. [cite: 4]
• US20110129538A1 (Publication Date: 2011-06-02, Assignee: Boehringer Ingelheim International Gmbh, Title: Process for preparing orally administered dabigatran formulations). This patent concerns processes for preparing dabigatran formulations and could be broadly relevant to manufacturing aspects, but its specific relevance to the compositional claims of US11013729 would depend on the details of the processes described. [cite: 4]
• WO2012001156A2 (Publication Date: 2012-01-05, Assignee: Krka, Tovarna Zdravil, D.D., Novo Mesto, Title: Pharmaceutical oral dosage forms comprising dabigatran etexilate and its pharmaceutically acceptable salts). This patent describes other oral dosage forms of dabigatran etexilate, indicating continued development in this area prior to US11013729. [cite: 4]

Obviousness Analysis under 35 U.S.C. § 103 for US Patent 11013729

An invention is obvious under 35 U.S.C. § 103 if the differences between the claimed invention and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art (PHOSITA). This analysis considers: (1) the scope and content of the prior art; (2) the differences between the claimed invention and the prior art; (3) the level of ordinary skill in the pertinent art; and (4) secondary considerations of non-obviousness.

1. Independent Claims

The independent claims of US 11013729 are Claims 1, 11, and 16. Their key elements are:

• Claim 1: A composition comprising a mixture of at least two distinct types of particles. The first type comprises dabigatran etexilate (or its pharmaceutically acceptable salt/polymorph) and is free from organic and inorganic acids. The second type comprises at least one pharmaceutically acceptable organic acid, is coated with a protective coating layer, and is free from dabigatran etexilate.
• Claim 11: A composition consisting of a mixture of two distinct types of particles (as defined in Claim 1) and at least one pharmaceutically acceptable excipient.
• Claim 16: A capsule containing a pharmaceutical composition consisting of a mixture of two distinct types of particles (as defined in Claim 1) and at least one pharmaceutically acceptable excipient.

The core inventive concept across these claims is the physical separation of acid-sensitive dabigatran etexilate into one particle type (which is acid-free) and a pharmaceutically acceptable organic acid into a second, distinct particle type (which is coated and active-free), followed by mixing these two particle types.

2. Scope and Content of the Prior Art

The patent itself identifies several relevant prior art documents:

• U.S. Patent Application 2006/0183779A1: This application describes pharmaceutical compositions of dabigatran etexilate mesylate (DEM) for oral administration in the form of pellets. These pellets comprise an acidic core (e.g., tartaric acid) and an active substance layer (DEM) that encloses the core. Optionally, a separating agent layer is placed between the acid core and the active layer, and the active layer may be further enclosed in an outer coating. The patent states that "the process of preparing layered pellets is cumbersome, time consuming and uneconomical."
• U.S. Patent Application 2005/0038077 (and WO 03/074056): This application discloses a tablet containing dabigatran etexilate (or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable organic acids. The patent criticizes this approach, stating that "due to the presence of an organic acid in close contact with the active in a tablet composition without any special steps taken to separate the two from each other, can make the active highly susceptible to hydrolysis in the presence of humidity." Example 3 of US 11013729 explicitly refers to "Formulation B" as being prepared according to WO 03/074056, particularly Example 1, which represents a formulation having "one type of particles/pellets having both dabigatran etexilate mesylate and organic acid."
• WO98/37075: First disclosed dabigatran.
• WO 2005/028468: Describes anhydrous polymorphic forms I and II of dabigatran etexilate mesylate.

General knowledge in the art at the time of the invention (priority date 2012-02-21) would include common pharmaceutical excipients, granulation techniques (wet, dry, melt), extrusion-spheronization for pellets, and various coating methods and materials for taste-masking, protection, or controlled release.

3. Differences Between the Claimed Invention and the Prior Art

The primary difference lies in the physical arrangement of the active pharmaceutical ingredient (dabigatran etexilate) and the organic acid.

• U.S. Patent Application 2005/0038077 / WO 03/074056 teaches compositions where dabigatran etexilate and the organic acid are in direct contact within a single particle type (e.g., a tablet or a pellet where both are mixed).
• U.S. Patent Application 2006/0183779A1 teaches layered pellets where an active substance layer encloses an acid core, potentially with an intermediate separating layer and an outer coating. This still constitutes a single composite particle with the acid and active in close proximity, even if separated by a thin layer.

In contrast, US 11013729 claims a mixture of at least two distinct types of particles: one containing the active (acid-free) and a separate one containing the organic acid (active-free and coated).

4. Level of Ordinary Skill in the Art (PHOSITA)

A PHOSITA in the field of oral pharmaceutical formulations at the time of the invention would likely have a Master's or Ph.D. in pharmaceutical sciences, chemistry, or a related field, with practical experience in drug development, formulation, and manufacturing. They would be familiar with the physicochemical properties of drugs, including pH-dependent solubility, stability issues (e.g., hydrolysis), and techniques to address these challenges in oral dosage forms. They would also understand the role of organic acids in enhancing the bioavailability of certain drugs and various methods for particle preparation and coating.

5. Motivation to Combine/Modify Prior Art

The background of US 11013729 clearly articulates the problems associated with dabigatran etexilate, stating that it "predominantly undergoes degradation by hydrolytic pathways in the presence of moisture" and is "acid sensitive."

The patent itself provides the motivation for a PHOSITA to combine or modify the existing prior art:

1. Addressing Instability due to Direct Acid Contact: U.S. Patent Application 2005/0038077 is explicitly criticized for allowing "an organic acid in close contact with the active," leading to the active being "highly susceptible to hydrolysis in the presence of humidity." A PHOSITA, faced with this known problem of dabigatran etexilate's acid sensitivity, would be motivated to physically separate the active from the organic acid. Instead of merely using a separating layer within a single particle (as in some embodiments of US 2006/0183779A1), creating entirely distinct particles for each component would be an obvious way to maximize this separation and minimize direct contact.
2. Improving upon "Cumbersome" Layered Pellets: U.S. Patent Application 2006/0183779A1 teaches layered pellets, which the present patent describes as "cumbersome, time consuming and uneconomical." A PHOSITA would seek simpler, more efficient manufacturing processes. Preparing two separate particle types (e.g., by granulation and/or extrusion-spheronization, as described in the present patent's examples) and then blending them is a well-known and often simpler approach compared to multi-layer coating processes.
3. Benefits of Organic Acid Maintenance: Both U.S. Patent Application 2006/0183779A1 and U.S. Patent Application 2005/0038077 acknowledge the benefit of including an organic acid with dabigatran etexilate for its pH-dependent solubility characteristics. The motivation would be to retain this beneficial effect while mitigating the stability issues.
4. Known Pharmaceutical Techniques: Coating of particles (including acid pellets) is a standard technique in pharmaceutical formulation to protect components, control release, or mask taste. Given the acid sensitivity of dabigatran etexilate and its proneness to hydrolytic degradation, a PHOSITA would be motivated to protect the more vulnerable component or prevent unwanted interactions. Coating the organic acid particles, as claimed, would prevent the acid from readily interacting with the dabigatran etexilate particles or with moisture in the environment, further enhancing overall stability while still providing the acidic microenvironment upon dissolution.
5. Achieving Faster Dissolution: The patent itself states a goal of providing "quick dissolution particularly at earlier time points" to enhance active absorption., A PHOSITA would understand that different particle sizes and formulations can influence dissolution profiles. Creating separate, optimized particles could be a way to achieve a desired dissolution characteristic.

Specific Combinations:

• U.S. Patent Application 2005/0038077 (or WO 03/074056) + General Knowledge of Dabigatran Stability + Standard Coating Techniques: Given the explicit problem of instability caused by direct contact between dabigatran etexilate and organic acid in a single formulation (as taught by US'077 and exemplified by Formulation B), a PHOSITA would be motivated to separate these components. Creating distinct particles for the active and the acid, and further coating the acid particles (a well-known protective measure), would be an obvious way to overcome the identified stability issues while retaining the benefit of the acid environment upon dissolution.
• U.S. Patent Application 2006/0183779A1 + General Knowledge of Manufacturing Efficiency & Particle Formulation: Recognizing the "cumbersome" nature of layered pellets from US'779, a PHOSITA would seek a simpler manufacturing method that still provides the benefits of acid. Producing separate active-containing granules and coated acid pellets, then blending them, would be an obvious alternative approach to achieve component separation and enhance stability without the complexity of multi-layering within a single particle.

6. Secondary Considerations

The patent presents an "unexpected result" in Example 3, demonstrating that "Formulation A" (the claimed invention with two distinct types of particles) provides "faster dissolution particularly at earlier time points as compared to formulation having one type of particles/pellets (Formulation B)." For instance, at 10 minutes, Formulation A released 65.1% of the active, while Formulation B released only 19.2%. This improved early dissolution profile is presented as an advantage, ensuring "availability of more amount of active especially when (a) absorption of the active is rapid... (b) significant bioactivation is involved and (c) negligible and variable absorption at higher pH.",

While the motivation for separating the active and acid to improve stability and simplify manufacturing seems apparent to a PHOSITA, the significantly faster dissolution at earlier time points shown in Example 3 could be argued as an unexpected result, potentially weighing against a finding of obviousness. However, faster dissolution can sometimes be an expected outcome of certain particle formulations and coatings. The extent to which this specific improvement is truly "unexpected" would be a key point of contention.

To provide a comprehensive overview of US Patent 11013729, I will detail its patent term adjustments (PTA), patent term extensions (PTE), continuation applications, divisional applications, related family members, and projected expiration date.

Patent Term Adjustments (PTA) and Extensions (PTE):

• Patent Term Adjustment (PTA): The Google Patents page for US11013729 does not explicitly list a Patent Term Adjustment. PTA is an extension of the patent term to compensate for administrative delays by the USPTO during patent prosecution, which applies to applications filed on or after May 29, 2000.
• Patent Term Extension (PTE): The Google Patents page for US11013729 does not explicitly list a Patent Term Extension. PTE is available for patents on certain human drugs, food or color additives, medical devices, animal drugs, and veterinary biological products to restore time lost during premarket government approval from a regulatory agency like the FDA.

Continuation and Divisional Applications:

• Continuation Applications: A continuation application is filed for an invention disclosed in a prior, co-pending non-provisional application, where the disclosure does not introduce new subject matter.
  • US Patent 11013729 is listed as being a parent application to US17/241,793, which is an active continuation application (US11752142B2).
  • US Patent 11013729 is also a parent to US18/356,642, which is a pending continuation application (US20240139168A1).
• Divisional Applications: A divisional application is filed when an original application is determined to contain more than one patentable invention, allowing the applicant to pursue claims directed to the unelected inventions in a separate application. There is no explicit mention of divisional applications directly stemming from US11013729 in the provided text.

Related Family Members:

The Google Patents page indicates the following related family members:

• Applications Claiming Priority:
  • IN461/MUM/2012 (Priority Date: 2012-02-21)
  • PCT/EP2013/053426 (WO2013124340A1) (Priority Date: 2012-02-21, Filing Date: 2013-02-21)
• Related Parent Applications:
  • PCT/EP2013/053426 (WO2013124340A1) (Priority Date: 2012-02-21, Filing Date: 2013-02-21)
• Related Child Applications:
  • US17/241,793 (Continuation, US11752142B2) (Priority Date: 2012-02-21, Filing Date: 2021-04-27)
• Family Applications (including US11013729B2 itself):
  • US14/379,613 (US11013729B2) (Priority Date: 2012-02-21, Filing Date: 2013-02-21)
  • US17/241,793 (US11752142B2) (Priority Date: 2012-02-21, Filing Date: 2021-04-27)
  • US18/356,642 (US20240139168A1) (Priority Date: 2012-02-21, Filing Date: 2023-07-21)
• Country Status (Examples of patents granted in other countries):
  • EP2817000B1
  • JP6215239B2
  • KR102090242B1
  • CN110123774A
  • AU2013224146B2
  • BR112014020474B1
  • CA2864423C

Projected Expiration Date:

The Google Patents page for US11013729 indicates that its legal status is "Active" and it "expires 2034-01-08". This expiration date is likely an "Adjusted expiration" date, factoring in any PTA.

Defensive Disclosure: Derivative Variations of US Patent 11013729

This document outlines derivative variations of the oral pharmaceutical compositions claimed in US Patent 11013729, focusing on the core inventive concept of separating dabigatran etexilate from organic acids into distinct particle types. These disclosures aim to establish prior art for future incremental improvements by rendering them obvious or non-novel.

Core Claim Addressed: Claim 1

Claim 1 describes a composition comprising a mixture of at least two distinct types of particles: a first type comprising dabigatran etexilate (free from organic/inorganic acids) and a second type comprising at least one pharmaceutically acceptable organic acid (coated with a protective coating layer and free from dabigatran etexilate).

---

Derivative Variations

1. Material & Component Substitution

Derivative 1.1: Self-Emulsifying Solid Dispersion for Dabigatran Etexilate Particles

• Enabling Description: The first type of particles, comprising dabigatran etexilate mesylate, is prepared as a solid self-emulsifying drug delivery system (S-SEDDS). Dabigatran etexilate mesylate is dissolved or dispersed in a mixture of pharmaceutically acceptable lipids (e.g., Capmul® MCM, Labrafil® M 1944 CS) and non-ionic surfactants (e.g., Cremophor® RH40, Tween® 80), with a hydrophilic binder (e.g., Kollidon® VA64) and a superdisintegrant (e.g., Explotab®) acting as a solid carrier. This molten mixture is spray-dried or melt-extruded onto inert spherical carriers (e.g., microcrystalline cellulose spheres) to form granules. This process ensures enhanced solubility and bioavailability by forming a fine emulsion in the gastrointestinal tract, while maintaining the acid-free characteristic of the dabigatran-containing particles. The resulting S-SEDDS granules typically have a particle size distribution of 100-500 microns.

• flowchart TD
      A[Dabigatran Etexilate Mesylate] --> B(Lipids + Surfactants)
      B --> C{Homogenize & Heat}
      C --> D[Melt Mixture]
      E[Hydrophilic Binder + Superdisintegrant] --> F(Inert Spherical Carriers)
      D --Spray Dry or Melt Extrude onto--> F
      F --> G[S-SEDDS Granules]
      G --Free from Acids--> H(First Type Particles)
  

Derivative 1.2: Phytic Acid Coated Pellets for Acid Component

• Enabling Description: The second type of particles comprises phytic acid (inositol hexakisphosphate) as the pharmaceutically acceptable organic acid. Phytic acid, known for its chelating properties and lower intrinsic water solubility compared to tartaric acid, is granulated with a suitable binder (e.g., polyvinylpyrrolidone K30) and diluent (e.g., calcium phosphate dibasic anhydrous) via wet granulation, followed by extrusion-spheronization to form spherical pellets (target size: 400-800 microns). These phytic acid pellets are then coated with a protective layer composed of a polymethacrylate copolymer (e.g., Eudragit® FS 30 D) combined with a plasticizer (e.g., triethyl citrate) and an anti-tacking agent (e.g., talc) via fluid bed coating. This coating is designed to resist gastric pH and release the phytic acid in the intestinal environment, ensuring separation from the dabigatran etexilate until appropriate physiological conditions are met, thus preventing premature hydrolysis.

• graph TD
      A[Phytic Acid] --> B(Binder + Diluent)
      B --Wet Granulation--> C{Wet Mass}
      C --Extrusion-Spheronization--> D[Phytic Acid Pellets]
      E[Polymethacrylate Copolymer] --> F(Plasticizer + Anti-tacking Agent)
      F --Fluid Bed Coating--> G[Protective Coating Layer]
      D --Coated with--> G
      G --> H(Second Type Particles)
      H --Free from Dabigatran Etexilate--> I(Coated Phytic Acid Pellets)
  

Derivative 1.3: Cellulose Acetate Phthalate (CAP) Protective Coating

• Enabling Description: The protective coating layer for the second type of particles (organic acid pellets) is formulated using cellulose acetate phthalate (CAP) as the primary film-forming polymer. CAP is dissolved in an organic solvent system (e.g., acetone/isopropyl alcohol mixture) along with a suitable plasticizer (e.g., diethyl phthalate) to ensure film flexibility. This coating solution is applied to the organic acid pellets (e.g., tartaric acid pellets) in a fluid bed coater. CAP provides an enteric coating that remains intact in acidic gastric fluid (pH < 4.5) and rapidly dissolves at higher intestinal pH, ensuring that the organic acid is released distal to the stomach, thus minimizing any potential contact with dabigatran etexilate in the upper gastrointestinal tract before the protective effect of acid is required for optimal absorption. The coating is applied to a weight gain of 5-15% by weight of the pellets.

• stateDiagram
      direction LR
      State1: Organic Acid Pellet
      State2: CAP Coating Application
      State3: Drying
      State4: Coated Pellet (Gastric Stable)
      State5: Intestinal pH (~6.0)
      State6: CAP Dissolves
      State7: Organic Acid Release
      State1 --> State2: Coating Process
      State2 --> State3: Solvent Evaporation
      State3 --> State4: Formation of Protective Layer
      State4 --> State5: Ingestion & Gastric Passage
      State5 --> State6: pH Triggered Dissolution
      State6 --> State7: Controlled Release
  

2. Operational Parameter Expansion

Derivative 2.1: Nanoparticulate Dabigatran and Micro-Tablet Acid Components

• Enabling Description: The first type of particles comprises dabigatran etexilate mesylate formulated as nanoparticles, with a mean particle size ranging from 50 nm to 200 nm, stabilized by a non-ionic surfactant (e.g., Polysorbate 80) and a polymeric stabilizer (e.g., Soluplus®) using wet media milling or high-pressure homogenization. These nanoparticles are then spray-dried with a suitable diluent (e.g., mannitol) to form flowable powder granules of 50-150 microns. The second type of particles consists of compressed micro-tablets (1 mm to 3 mm diameter) of tartaric acid blended with a disintegrant (e.g., croscarmellose sodium) and a binder (e.g., pregelatinized starch). These micro-tablets are then film-coated with a moisture-barrier polymer (e.g., ethylcellulose) to ensure stability and separation from the dabigatran nanoparticles. This combination allows for extremely rapid initial dissolution of dabigatran nanoparticles and a precisely controlled, delayed release of the acidifier.

• graph LR
      A[Dabigatran Etexilate Mesylate] --> B(Nanoparticle Formation: 50-200nm)
      B --Spray Dry with Mannitol--> C[First Type Granules: 50-150µm]
      D[Tartaric Acid + Disintegrant + Binder] --> E(Micro-tablet Compression: 1-3mm)
      E --Film Coating (Ethylcellulose)--> F[Second Type Micro-tablets]
      C & F --> G{Capsule Filling: Mixture}
  

Derivative 2.2: Multi-Layered Enteric Coating with pH-Triggered Burst Release

• Enabling Description: The second type of particles (organic acid pellets) is equipped with a multi-layered protective coating for precision pH-triggered burst release. The innermost layer is a moisture barrier (e.g., Opadry® AMB) to protect the acid core. Over this, an intermediate layer of a pH-dependent polymer (e.g., Eudragit® L 30 D-55, dissolving at pH > 5.5) is applied. The outermost layer is a rapidly dissolving polymer (e.g., hydroxypropylmethylcellulose) containing a pore-forming agent (e.g., polyethylene glycol) and an effervescent agent (e.g., sodium bicarbonate). Upon dissolution of the outermost layer in the stomach, water penetrates to the intermediate enteric layer. Once the pH environment reaches approximately 5.5-6.0 in the duodenum, the intermediate layer rapidly dissolves, and the effervescent agent instantly releases CO2, causing a rapid disintegration of the remaining coating and a burst release of the organic acid. This ensures a precisely timed acidic microenvironment for optimal dabigatran absorption.

• graph TD
      A[Organic Acid Pellet] --> B(Moisture Barrier Layer)
      B --> C(pH-Dependent Enteric Layer: Eudragit L 30 D-55)
      C --> D(Rapid Dissolving Layer with Pore/Effervescent Agents)
      D --> E[Multi-Layer Coated Pellet]
      E --Gastric Passage (pH < 5.5)--> F{Outer Layer Dissolves}
      F --> G{Intermediate Layer Intact}
      G --Duodenal Passage (pH > 5.5)--> H{Intermediate Layer Dissolves & Burst Release}
  

Derivative 2.3: Continuous Hot-Melt Extrusion Manufacturing

• Enabling Description: The manufacturing process for both particle types is implemented using continuous hot-melt extrusion (HME) technology. For the first type of particles, dabigatran etexilate mesylate is dry blended with a melt-extrudable polymer (e.g., Kollidon® VA64, Soluplus®) and a plasticizer (e.g., polyethylene glycol 6000). This blend is fed into a twin-screw extruder operating at elevated temperatures (e.g., 120-150°C) and then cooled and milled to form granules of 200-800 microns, ensuring acid-free composition. For the second type, the pharmaceutically acceptable organic acid (e.g., citric acid) is similarly melt-extruded with a melt-extrudable polymer (e.g., Ethocel™ Standard 10 Premium, Surelease®) acting as a sustained-release matrix. The resulting extrudate is then spheronized and coated in-line with a protective layer using an integrated fluid bed coater before final milling and screening, ensuring the dabigatran-free and coated properties. This HME-based approach enhances process efficiency and content uniformity.

• flowchart LR
      A[Dabigatran + Polymer + Plasticizer] --> B(HME - Extruder 1)
      B --> C(Cooling & Milling)
      C --> D[Dabigatran Granules (First Type)]
      E[Organic Acid + Polymer] --> F(HME - Extruder 2)
      F --> G(Spheronization)
      G --> H(In-line Fluid Bed Coater)
      H --> I[Coated Acid Pellets (Second Type)]
      D & I --> J{Blending & Encapsulation}
  

3. Cross-Domain Application

Derivative 3.1: Soil Amendment for Nutrient Release in AgTech

• Enabling Description: A soil amendment composition designed to optimize nutrient availability for plants in pH-sensitive environments. The first type of particles contains a pH-sensitive micronutrient (e.g., iron chelate that becomes insoluble at high pH) stabilized with a non-acidic polymer matrix (e.g., starch-based biodegradable polymer), with a particle size of 200-1000 microns, ensuring the iron chelate is not immediately exposed to acid. The second type of particles comprises a slow-release organic acid (e.g., humic acid or fulvic acid embedded in a lignin-based hydrophobic coating), also with a particle size of 200-1000 microns. This protective coating prevents premature acid release. When applied to alkaline soils, moisture penetrates the coated acid particles over time, slowly releasing the acid to create localized acidic microenvironments, which solubilize the micronutrient from the first type of particles, making it bioavailable to plant roots.

• graph TD
      A[pH-Sensitive Micronutrient] --> B(Non-Acidic Polymer Matrix)
      B --> C[Nutrient Particles (First Type)]
      D[Humic/Fulvic Acid] --> E(Lignin-based Hydrophobic Coating)
      E --> F[Acid Particles (Second Type)]
      C & F --> G{Soil Application Mixture}
      G --Moisture Penetration (Slow)--> H{Acid Release (Localized)}
      H --> I{Micronutrient Solubilization}
  

Derivative 3.2: Oral Vaccine Delivery for Aquatic Animals

• Enabling Description: An oral vaccine delivery system for aquatic animals (e.g., fish in aquaculture) targeting enteric pathogens. The first type of particles contains a live attenuated vaccine strain (e.g., bacterial antigens) encapsulated in an alginate-chitosan matrix that is free from organic acids. The second type of particles contains a feed-grade organic acid (e.g., formic acid salt, e.g., sodium formate) incorporated into a lipid-based pellet and coated with a gastric-resistant polymeric coating (e.g., shellac or zein). These coated acid particles are designed to release the acid upon reaching the posterior gut, creating an acidic environment conducive to the stability and uptake of the live vaccine, which is released from the first type of particles as the alginate-chitosan matrix degrades, thereby bypassing gastric degradation.

• sequenceDiagram
      participant Fish as Fish Intestine
      actor Pellet as Mixed Pellets
      Pellet->>Fish: Ingestion
      Fish->>Pellet: Gastric Passage
      Pellet->>Acid_Particle: Gastric Resistant Coating Intact
      Pellet->>Vaccine_Particle: Alginate-Chitosan Matrix Intact
      Fish->>Acid_Particle: Posterior Gut pH
      Acid_Particle->>Acid_Particle: Coating Dissolves
      Acid_Particle->>Acid_Particle: Formic Acid Release
      Acid_Particle-->>Vaccine_Particle: Local Acidification
      Vaccine_Particle->>Vaccine_Particle: Alginate-Chitosan Degradation
      Vaccine_Particle->>Fish: Vaccine Antigen Release & Uptake
  

Derivative 3.3: Humidity-Activated Deodorizer for Consumer Electronics

• Enabling Description: A humidity-activated deodorizing insert for consumer electronics (e.g., internal components of air purifiers or humidifiers). The first type of particles comprises a pH-sensitive malodor adsorbate or neutralizing agent (e.g., certain metal oxides or amines) encapsulated in a moisture-permeable but acid-free polymer. The second type of particles contains an encapsulated organic acid (e.g., citric acid encapsulated in a hygroscopic, slow-dissolving polymer like polyvinyl alcohol) with a protective coating. In high-humidity conditions (e.g., inside an operating humidifier), the coating on the acid particles slowly dissolves, releasing the organic acid, which then interacts with the acid-sensitive malodor adsorbate particles. This interaction (e.g., pH change, direct chemical reaction) enhances the deodorizing capacity of the first particle type, providing an on-demand, humidity-controlled odor neutralization system without premature activation in dry conditions.

• stateDiagram
      direction LR
      State1: Dry Environment
      State2: High Humidity
      State3: Acid Coating Dissolves (Slowly)
      State4: Organic Acid Release
      State5: Adsorbate/Neutralizer Particles
      State6: Enhanced Deodorization
      State1 --> State5: Dormant
      State1 --> State2: Humidity Increase
      State2 --> State3: PVA Coating Activation
      State3 --> State4: Citric Acid Release
      State4 --> State6: Interaction with State5
      State5 --> State6: Increased Activity
  

4. Integration with Emerging Tech

Derivative 4.1: AI-Optimized Fluid Bed Granulation and Coating

• Enabling Description: An autonomous manufacturing system for the dabigatran etexilate composition, leveraging AI-driven optimization. The fluid bed granulation (for dabigatran particles) and fluid bed coating (for organic acid pellets) processes are equipped with in-line process analytical technology (PAT) sensors including NIR spectroscopy for active pharmaceutical ingredient (API) content and moisture, laser diffraction for real-time particle size distribution, and acoustic sensors for granule morphology. Data from these sensors are continuously fed into a predictive AI model (e.g., a recurrent neural network) that has been trained on historical batch data and optimal dissolution profiles. The AI model dynamically adjusts critical process parameters (e.g., spray rate, atomization pressure, inlet air temperature, bed height, and coating solution viscosity) in real-time, within predefined quality by design (QbD) parameters, to maintain optimal product quality, minimize waste, and ensure consistent in-vitro release characteristics without human intervention for fine adjustments.

• flowchart TD
      A[Raw Materials] --> B(Fluid Bed Granulator/Coater)
      B --In-line PAT Sensors--> C{Real-time Data Stream}
      C --> D[AI Optimization Engine]
      D --Parameter Adjustment Feedback--> B
      B --> E[Optimized Particle Output]
      E --> F{Final Blending & Encapsulation}
      D --Predictive Analytics & Model Update--> G(Data Lake/Historical Data)
  

Derivative 4.2: IoT-Enabled Smart Capsule for In-Vivo Monitoring

• Enabling Description: The oral pharmaceutical composition is delivered via an IoT-enabled "smart capsule." The organic acid pellets are individually embedded with micro-pH sensors (e.g., miniaturized solid-state ion-selective field-effect transistors, ISFETs) and a micro-transmitter, powered by a biocompatible micro-battery. Upon ingestion, these sensors continuously monitor the pH conditions within the gastrointestinal tract at the point of acid release. The first type of particles (dabigatran etexilate) remains acid-free. The real-time pH data, along with location data (if using ingestible RFID or localization technologies), is wirelessly transmitted to an external wearable receiver or smartphone application. This allows for precise, patient-specific correlation of acid release timing with physiological pH, enabling physicians to tailor dosing regimens or dietary advice based on individual gastric emptying and intestinal transit times, and potentially detect malabsorption issues.

• classDiagram
      class Smart_Capsule {
          +DabigatranParticles
          +CoatedAcidPellets
      }
      class CoatedAcidPellets {
          +OrganicAcid
          +ProtectiveCoating
          +MicroPHSensor
          +MicroTransmitter
          +MicroBattery
      }
      class ExternalReceiver {
          +WirelessAntenna
          +DataLogger
          +SmartphoneAppInterface
      }
      Smart_Capsule "1" -- "N" CoatedAcidPellets : contains
      CoatedAcidPellets <.. ExternalReceiver : Transmits pH data
      ExternalReceiver <.. Patient : Personalized Feedback
  

Derivative 4.3: Blockchain-Verified Ingredient Traceability

• Enabling Description: A comprehensive blockchain-based system is deployed to ensure the integrity and traceability of all raw materials (dabigatran etexilate mesylate, organic acid, excipients, coating polymers) and the finished two-particle pharmaceutical composition. Each lot of raw material is assigned a unique cryptographic hash and registered on a private or consortium blockchain. Smart contracts automatically update the ledger at each stage of the supply chain (e.g., supplier, manufacturer, distributor, pharmacy). Quality control data (e.g., Certificates of Analysis, PAT data from Derivative 4.1) are also hashed and immutably linked to their respective material lots on the blockchain. Environmental monitoring data from IoT sensors during storage and transit (temperature, humidity, light exposure) are recorded as transactions. This provides an incorruptible audit trail, verifying the authenticity of each component, preventing counterfeiting, ensuring compliance with storage conditions, and enabling rapid recall if any quality deviations are detected.

• flowchart TD
      A[Raw Material Supplier] --> B{Cryptographic Hashing & Blockchain Entry}
      B --> C[Manufacturing Plant]
      C --QC Data & Process Records--> D{Smart Contract Update}
      D --> E[Distribution Center]
      E --IoT Environmental Data--> F{Smart Contract Update}
      F --> G[Pharmacy/Hospital]
      G --> H[Patient]
      subgraph Blockchain Network
          B---D---F
      end
  

5. The "Inverse" or Failure Mode

Derivative 5.1: pH-Induced Self-Degradation for Safety

• Enabling Description: A safety mechanism integrated into the dabigatran etexilate particles to induce controlled degradation under highly acidic conditions, preventing toxic accumulation in cases of accidental exposure or extreme physiological anomalies. The dabigatran etexilate particles (first type, acid-free) are formulated with a pH-sensitive auxiliary excipient (e.g., a small percentage of a basic polymer like polyethylenimine or an insoluble salt like magnesium oxide) finely dispersed within the granule. If these particles are prematurely exposed to an extremely low pH environment (e.g., pH < 1.0, indicative of a severe gastric upset or direct acid contact), the auxiliary excipient dissolves or reacts, creating localized microenvironments within the dabigatran particles that significantly accelerate the known hydrolytic degradation pathways of dabigatran etexilate into inactive metabolites. This "self-destruct" mechanism ensures that in potentially harmful, off-label exposure scenarios, the active drug is rapidly rendered inert, preventing systemic absorption of an uncontrolled dose.

• stateDiagram
      direction LR
      State1: Dabigatran Particle (Normal)
      State2: Exposure to Extreme Low pH (<1.0)
      State3: Auxiliary Excipient Reacts/Dissolves
      State4: Localized Microenvironment pH Shift
      State5: Accelerated Dabigatran Hydrolysis
      State6: Inactive Metabolites
      State1 --> State2: Aberrant Condition
      State2 --> State3: Trigger
      State3 --> State4: Cascade
      State4 --> State5: Degradation Path
      State5 --> State6: Safe Outcome
  

Derivative 5.2: Humidity-Triggered Low-Dose Release

• Enabling Description: The pharmaceutical composition is engineered to automatically adjust the release profile to a lower effective dose under conditions of high ambient humidity, anticipating potential moisture-induced degradation or altered patient physiology in humid climates. The protective coating on the organic acid pellets (second type) is designed with a hygroscopic, semi-permeable polymer (e.g., a blend of ethylcellulose and a high-molecular-weight polyethylene glycol) that becomes significantly more permeable to water vapor above a critical relative humidity (e.g., >75% RH). In such high-humidity storage conditions, water penetrates the coating at an accelerated rate, causing a partial or slower release of the organic acid over an extended period. This slower acid release, in turn, leads to a delayed or attenuated overall dissolution rate of dabigatran etexilate in vivo, effectively delivering a "low-power" or reduced functional dose. This mechanism acts as an inherent safety feature, potentially mitigating the risk of over-exposure if the product's stability or patient's metabolic capacity is compromised in tropical or highly humid environments.

• stateDiagram
      direction LR
      State1: Coated Acid Pellet (Normal)
      State2: High Ambient Humidity (>75% RH)
      State3: Hygroscopic Coating Permeability Increases
      State4: Water Ingress into Pellet (Accelerated)
      State5: Slower Organic Acid Release Profile
      State6: Attenuated Dabigatran Dissolution (In Vivo)
      State7: Lower Effective Dose
      State1 --> State2: Environmental Trigger
      State2 --> State3: Coating Response
      State3 --> State4: Water Absorption
      State4 --> State5: Acid Release Modification
      State5 --> State6: Downstream Impact
      State6 --> State7: Functional Adjustment
  

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Combination Prior Art Scenarios with Open-Source Standards

These scenarios illustrate how the inventive composition, as described in US11013729, can be combined with existing open-source pharmaceutical standards, making any claims encompassing these standard practices obvious.

1. Combination with USP <711> Dissolution Testing Standards

• Scenario: A pharmaceutical composition comprising the two distinct particle types of dabigatran etexilate and a pharmaceutically acceptable organic acid, formulated into a capsule, wherein the dissolution profile of said composition is characterized and controlled according to the procedures outlined in the United States Pharmacopeia (USP) General Chapter <711> Dissolution. Specifically, the composition demonstrates a dissolution rate of not less than 60% of dabigatran etexilate mesylate released within 15 minutes when tested in 0.01N HCl pH 2.0 dissolution media at 37±0.5°C using a USP Apparatus 1 (basket apparatus) at a stirring speed of 100 revolutions per minute (rpm), with samples analyzed by UV-Vis spectrophotometry or High-Performance Liquid Chromatography (HPLC) in compliance with USP analytical methods.

2. Combination with ICH Q1A(R2) Stability Testing Guidelines

• Scenario: A chemically and polymorphically stable oral pharmaceutical composition containing a mixture of the two distinct particle types (dabigatran etexilate-containing and coated organic acid-containing particles), prepared and packaged to demonstrate stability consistent with the International Council for Harmonisation (ICH) Q1A(R2) guideline on stability testing of new drug substances and products. This includes conducting accelerated stability studies at 40°C/75% relative humidity (RH) for 6 months and long-term stability studies at 25°C/60% RH or 30°C/65% RH for at least 12 months. Stability parameters such as assay of dabigatran etexilate, levels of degradation products (e.g., hydrolytic impurities), dissolution profiles, moisture content, and polymorphic form are monitored at specified time points using validated analytical methods compliant with ICH M10 (Bioanalytical Method Validation).

3. Combination with ISO 13320 (Particle Size Analysis - Laser Diffraction Methods)

• Scenario: A pharmaceutical composition containing two distinct types of particles, where the first type of particles (comprising dabigatran etexilate) and the second type of particles (comprising a pharmaceutically acceptable organic acid) are characterized for their particle size distribution using laser diffraction, in accordance with the International Organization for Standardization (ISO) 13320:2020 standard. The particle size distribution of both particle types (e.g., D10, D50, D90 values) is determined by dispersing samples in a suitable non-solubilizing liquid (e.g., mineral oil or isopropyl alcohol for dry powders/granules) with appropriate sonication and stirring, and analyzed using either Fraunhofer or Mie scattering theories, depending on particle opacity and size range, to ensure compliance with predefined specifications for optimal processing and in-vivo performance.