IPR2025-00799
`U.S. Patent 11,261,151
`TUNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`INTAS PHARMACEUTICALS LTD.,
`Petitioner
`
`v.
`
`ATOSSA THERAPEUTICS, INC.,
`Patent Owner
`______________________
`Case IPR2025-00799
`Patent 11,261,151
`______________________
`
`PATENT OWNER’S REQUEST FOR DISCRETIONARY DENIAL
`OF INSTITUTION
`
`

`

`
`
`LIST OF EXHIBITS
`
`Exhibit
`
`EX2001
`
`EX2002
`
`EX2003
`
`EX2004
`
`EX2005
`
`EX2006
`
`EX2007
`
`EX2008
`
`EX2009
`
`EX2010
`
`EX2011
`
`EX2012
`
`ATOSSA THERAPEUTICS, INC. QUARTERLY REPORT FORM
`10-Q for the Quarterly Period Ended March 31, 2025
`Atossa Therapeutics Proposes Potentially Groundbreaking Study
`Aimed at Reducing Interval Breast Cancer in High-Risk Womenat
`AACR2025 (April 29, 2025
`Atossa Therapeutics Announces Plans to Pursue Metastatic Breast
`CancerIndication for (Z)-Endoxifen and Continued Engagementwith
`FDAon Additional Indications
`(March 11, 2025
`Financials — Intas Pharmaceuticals Ltd.,
`http://www.intaspharma.com/financials/
`Atossa Therapeutics AnnouncesIssuance of Key U.S. Patent Covering
`Endoxifen (March 8, 2022
`Efficacy and Safety of Endoxifen in Bipolar I Disorder Patients,
`NCT06608641 (Last Updated March 17, 2025),
`https://clinicaltrials.gov/study/NCT0660864 1
`Declaration of Sayem Osman
`Atossa Covenant Notto Sue
`Atossa Therapeutics AnnouncesFull Results from Phase 2
`KARISMA-Endoxifen Study Demonstrating Statistically Significant
`Reductions in Mammographic Breast Density
`(Dec. 11, 2024
`Atossa Therapeutics AnnouncesFirst Quarter 2025 Financial Results
`and Provides a Corporate Update (May 13, 2025
`Intas Pharmaceuticals, Limited v. Atossa Therapeutics, Inc.,
`PGR2023-00043, EX1030
`Breast Center Year in Review, An Unmet Need in HR-Positive
`Endocrine-Resistant Breast Cancer, available at https://jons-
`online.com/special-issues-and-supplements/202 1/202 1-year-in-review-
`breast-cancer/an-unmet-need-in-hr-positive-endocrine-resistant-breast-
`cancer
`
`EX2013
`
`EX2014
`
`EX2015
`
`ATOSSA THERAPEUTICS, INC. ANNUAL REPORT FORM 10-K
`for the Fiscal Year Ended December 31, 2024
`U.S. Patent No. 11,572,334
`Intas Requirements for Resolving Disputes with Atossa (FILED
`UNDER SEAL
`
`EX2016
`
`Default Protective Order
`
`IPR2025-00799
`USS. Patent 11,261,151
`
`
`
`

`

`IPR2025-00799
`USS. Patent 11,261,151
`
`
`
`Exhibit
`EX2017
`
`EX2018
`
`EX2019
`
`EX2020
`
`EX2021
`
`EX2022
`
`Intas Pharmaceuticals, Limited v. Atossa Therapeutics, Inc.,
`PGR2025-00043, Pap.2 (Apr. 3, 2025
`Intas Pharmaceuticals, Limited v. Atossa Therapeutics, Inc.,
`PGR2023-00043, Pap.1 (Aug. 18, 2023
`Rishab Gupta & Swarndeep Singh, Endoxifen Approvalfor Bipolarin
`India, A Premature or a Pragmatic Decision?, 43(1) J. CLINICAL
`PSYCHOPHARMACOLOGY3 (2023
`Zonalta, Why Zonalta?, available at https://zonalta.in/
`Atossa Therapeutics Granted Additional Patent Protection for
`Endoxifen (August 28, 2024
`Declaration of Megan Raymond
`
`
`
`

`

`IPR2025-00799
`U.S. Patent 11,261,151
`
`TABLE OF CONTENTS
`
`
`
`I.
`Introduction ...................................................................................................... 1
`The ’151 Patent: A Lifeline for Breast Cancer Patients .................................. 4
`II.
`III. The Parties ....................................................................................................... 7
`IV. The Board May Take Into Account All Relevant Considerations in
`Exercising its Discretion to Deny Institution .................................................. 9
`A. Compelling Public Health Interests Support Discretionary Denial ......... 9
`B. This Proceeding Would Waste the Board’s Resources Given Patent
`Owner’s Stipulation Not to Sue for Infringement .................................14
`C. Patent Owner’s Settled Expectations Deserve Protection Where
`Petitioner Challenged a Related Patent in 2023 but Delayed in Filing
`This Challenge .......................................................................................17
`D. The Board Should Additionally Deny Institution Under 35 U.S.C.
`§325(d) Because the Office Has Already Rejected the Same Art During
`Prosecution .............................................................................................19
`E. The Merits Are Weak .............................................................................24
`1.
`Petitioner’s Inherency Arguments Are Legally Insufficient ...24
`2.
`Collateral Estoppel Does Not Apply and Does Not Fix the Gap
`Caused by the Petition’s Failed Inherency Arguments .............33
`F. Petitioner’s Excessive Reliance on Expert Testimony Highlights
`Factual Disputes Unsuited for IPR ........................................................34
`Conclusion .....................................................................................................36
`
`V.
`
`
`
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`
`IPR2025-00799
`U.S. Patent 11,261,151
`
` Page(s)
`
`Cases
`Advanced Bionics, LLC v. Med-El Elektromedizinische Gerate GmbH,
`IPR2019-01469, Pap.6 (Feb. 13, 2020) .............................................................. 19
`Agilent Techs., Inc. v. Affymetrix, Inc.,
`567 F.3d 1366 (Fed. Cir. 2009) .......................................................................... 27
`Amazon.com, Inc. v. Vb Assets, LLC,
`IPR2020-01346, Pap.7 (Feb. 4, 2021) ................................................................ 23
`Apple Inc. v. Immervision, Inc.,
`IPR2023-00471, Pap.10 (July 11, 2023) ............................................................ 23
`Arbutus Biopharma Corp. v. Modernatx, Inc.,
`65 F.4th 656 (Fed. Cir. 2023) ............................................................................. 27
`Atrium Med. Corp. v. Bard Peripheral Vascular, Inc.,
`IPR2021-01197, Pap.11 (Jan. 10, 2022) ............................................................. 30
`Azurity Pharms., Inc. v. Exelixis Inc.,
`IPR2025-00210, Pap.11 (June 4, 2025) ........................................................ 26, 32
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Pap.8 (Dec. 15, 2017) .............................................................. 19
`Blackbird Tech LLC v. Health in Motion LLC,
`944 F.3d 910 (Fed. Cir. 2019) ............................................................................ 16
`Celltrion, Inc. v. Chugai Seiyaku Kabushiki Kaisha,
`IPR2022-00579, Pap.72 (Aug, 29, 2023) ........................................................... 26
`Cont’l Can Co. USA v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) .......................................................................... 29
`Crown Operations Int’l, Ltd. v. Solutia Inc.,
`289 F.3d 1367 (Fed. Cir. 2002) .......................................................................... 29
`cxLoyalty, Inc. v. Maritz Holdings Inc.,
`986 F.3d 1367 (Fed. Cir. 2021) .................................................................... 30, 36
`
`
`
`
`

`

`IPR2025-00799
`U.S. Patent 11,261,151
`
`Dabico Airport Sols., Inc. v. AXA Power ApS,
`IPR2025-00408, Pap.21 (June 18, 2025) ............................................................ 17
`Deere & Co. v. Int’l Harvester Co.,
`710 F.2d 1551 (Fed. Cir. 1983) .......................................................................... 15
`Glaxo Inc. v. Novopharm Ltd.,
`52 F.3d 1043 (Fed. Cir. 1995) ............................................................................ 31
`GoFire, Inc. v. Canopy Growth Corp.,
`PGR2020-00044, Pap.8 (Oct. 9, 2020) ............................................................... 20
`Google LLC v. Hammond Develop. Int’l, Inc.,
`54 F.4th 1377 (Fed. Cir. 2022) ........................................................................... 34
`iRhythm Techs., Inc. v. Welch Allyn, Inc.,
`IPR2025-00363,-00363,-00374,-00376,-00377,-00378, Pap.10
`(June 6, 2025)................................................................................................ 17, 35
`Millennium Pharms., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 26
`In re Montgomery,
`677 F.3d 1375 (Fed. Cir. 2012) .......................................................................... 26
`In re Oelrich,
`666 F.2d 578 (C.C.P.A. 1981) ............................................................................ 22
`OpenSky Indus. LLC v. VLSI Tech. LLC,
`IPR2021-01064, Pap.102 (Oct. 4, 2022) ............................................................ 16
`Par Pharm., Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 22
`Patent Quality Assurance, LLC, et al. v. VLSI Tech. LLC,
`IPR2021-01229, Pap.102 (Dec. 22, 2022) .......................................................... 16
`Pfizer, Inc. v. Chugai Pharm. Co,
`IPR2017-01357, Pap.56 (Nov. 28. 2018) ............................................... 27, 30, 31
`In Re Robertson,
`169 F.3d 743 (Fed. Cir. 1999) ............................................................................ 30
`
`
`
`i
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`IPR2025-00799
`U.S. Patent 11,261,151
`
`SmithKline Beecham Corp. v. Apotex Corp.,
`403 F.3d 1331 (Fed. Cir. 2005) .......................................................................... 27
`SNF S.A. v. Chevron U.S.A., Inc.,
`IPR2022-01534, Pap.46 (Apr. 18, 2024) ...................................................... 29, 33
`TikTok Inc. v NTECH Properties Inc.,
`IPR2024-01339, Pap.9 (Feb. 25, 2025) .............................................................. 36
`Trintec Indus., Inc. v. Top-U.S.A. Corp.,
`295 F.3d 1292 (Fed. Cir. 2002) .......................................................................... 30
`Verizon Servs. Corp. v. Cox Fibernet Va., Inc.,
`602 F.3d 1325 (Fed. Cir. 2010) .......................................................................... 26
`VirnetX Inc. v. Apple, Inc.,
`909 F.3d 1375 (Fed. Cir. 2018) .......................................................................... 33
`Xerox Corp. v. ByteMark, Inc.,
`IPR2022-00624, Pap.12 (Feb. 10, 2023) ............................................................ 36
`Statutes
`35 U.S.C. § 325(d) ................................................................................................... 19
`Other Authorities
`37 C.F.R. §42.65(a) ............................................................................................ 30, 36
`Fed. R. Evid. 408(a) ................................................................................................. 16
`Fed. R. Evid. 408(b) ................................................................................................. 16
`PTAB, FAQs for Interim Processes for PTAB Workload
`Management, https://www.uspto.gov/patents/ptab/faqs/interim-
`processes-workload-management ....................................................................... 34
`USPTO’s March 26, 2025 Memorandum on Interim Processes for
`PTAB Workload Management (“March 26 Guidance”) .............................passim
`
`
`
`
`
`ii
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`

`

`IPR2025-00799
`U.S. Patent 11,261,151
`
`I.
`
`Introduction
`The Petition challenging U.S. Patent No. 11,261,151 (“the ’151 Patent”;
`
`EX1001), a foundational patent owned by Atossa Therapeutics (“Atossa” or “Patent
`
`Owner”) covering a crystalline polymorph of (Z)-endoxifen, represents precisely the
`
`type of inefficient and unduly burdensome proceeding that the USPTO’s current
`
`policies seek to prevent. The ’151 Patent and its patent family relate to novel (Z)-
`
`endoxifen compositions, and include claims directed to, e.g., the treatment of
`
`hormone-dependent and tamoxifen-resistant breast cancer. This patent family is an
`
`important asset of Atossa and reflects years of focused research and clinical
`
`investment by a small American biopharmaceutical company to develop a stable,
`
`purified form of (Z)-endoxifen and to address a critical unmet need in hormone-
`
`sensitive breast cancer therapy. As explained below, discretionary denial is
`
`appropriate here pursuant to 35 U.S.C. §§ 314(a) and 325(d).
`
`The challenged claims are directed to a crystalline Form I of (Z)-endoxifen,
`
`defined by a specific x-ray powder diffraction (XRPD) fingerprint, as well as
`
`methods of using this highly pure polymorphic form. These claims are distinct from
`
`the claims of the previously adjudicated related patent, U.S. Patent No. 11,572,334
`
`(“the ’334 Patent”), which do not have any Form I or XRPD requirement. EX2014,
`
`cl.1. The (Z)-endoxifen claimed in the ’151 Patent provides a direct and reliable
`
`therapeutic alternative to tamoxifen, a decades-old standard of care that fails many
`
`PROTECTIVE ORDER MATERIAL
`
`1
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`

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`IPR2025-00799
`U.S. Patent 11,261,151
`patients due to metabolic limitations. As discussed below, Patent Owner is currently
`
`pursuing clinical trials on the use of a free base form of the claimed (Z)-endoxifen
`
`to treat breast cancer. Petitioner, in contrast, is appearenly involved in clinial trials
`
`using a salt form of (Z)-endoxifen in India to treat bipolar disorder and appears to
`
`be involved in clinical trials in the US using a salt form of (Z)-endoxifen to treat
`
`bipolar disorder.
`
`This IPR is not an isolated event. Instead, it is the latest in a series of
`
`coordinated attacks by Petitioner against Patent Owner’s intellectual property related
`
`to (Z)-endoxifen. Patent Owner is demonstrably a small entity, and relies almost
`
`entirely on external investment to fund its extensive research and clinical programs.
`
`And this Petition comes more than three years after patent issuance and amid
`
`ongoing Phase 2 and Phase 3 clinical trials built around the patented compound.
`
`As discussed below, every relevant factor under the USPTO’s March 26, 2025
`
`Memorandum on Interim Processes for PTAB Workload Management (“March 26
`
`Guidance”) demonstrates that discretionary denial is the proper outcome here.
`
`First, the public health implications are profound: Patent Owner’s business is
`
`focused on the treatment and prevention of breast cancer. Patent Owner is
`
`conducting multiple Phase 2 and 3 clinical trials targeting hormone-dependent and
`
`metastatic breast cancers using the claimed (Z)-endoxifen, and institution could
`
`disrupt and jeopardize access to these therapies for patients with few alternatives,
`
`
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`2
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`IPR2025-00799
`U.S. Patent 11,261,151
`particularly as Petitioner’s filing is part of a serial attack designed to burden and
`
`destabilize a small clinical-stage innovator.
`
`Second, institution here would be a needless waste of Patent Office and party
`
`resources. As discussed in more detail below and as reflected by the attached
`
`covenant, Patent Owner has provided a covenant not to sue Petitioner (or its
`
`affiliates or commercial partners) in the event Petitioner is able to bring its use of
`
`(Z)-endoxifen for treating bipolar disease to market. In light of this covenant, which
`
`eliminates any arguably legitimate commercial interest of Petitioner in challenging
`
`the ’151 Patent, this proceeding would be a waste of resources for the Board and
`
`Patent Owner.
`
`Third, Petitioner’s delay, including its decision to challenge a later-issued
`
`continuation patent in a PGR in 2023 while holding off and delaying this IPR for
`
`several years,
`
`is gamesmanship
`
`that undermines Patent Owner’s settled
`
`expectations.
`
`Fourth, discretionary denial is warranted here under 35 U.S.C. § 325(d). All
`
`of the art in Petitioner’s grounds was already substantively considered and rejected
`
`during prosecution. Liu (the only reference in Ground 1, and the primary reference
`
`in Ground 2) was explicitly used by the examiner in a rejection and Ahmad (the
`
`secondary reference in Ground 2) was cited in an IDS and discussed in the ’151
`
`patent’s specification. Further, there was no material error by the Examiner.
`
`
`
`3
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`IPR2025-00799
`U.S. Patent 11,261,151
`Fifth, the merits are exceptionally weak. Petitioner relies exclusively on
`
`inherency in attempt to show that Liu discloses the claimed Form I and XRPD
`
`pattern. But instead of relying on Liu’s actual disclosures, Petitioner reimagines,
`
`alters, and adds to Liu. Petitioner’s own expert, Dr. Bihovsky, initially failed to
`
`reproduce the claimed Form I of (Z)-endoxifen based on Liu and then was only able
`
`to obtain it after making no fewer than nine distinct deviations from Liu’s protocol,
`
`undermining any claim of “inherency” and highlighting the weakness of this
`
`challenge. This weakness impacts all of the grounds. Petitioner’s arguments about
`
`“collateral estoppel” are misplaced and do not save the Petition. The prior PGR
`
`involved different claims, different art, and did not address, let alone decide, the
`
`issues involving Form I, XRPD, or Liu’s “inherency” that are presented here.
`
`Sixth, the Petition’s excessive reliance on layered expert testimony to fill gaps
`
`and also to allege inherency through benchtop testing confirms that the factual issues
`
`raised here are ill-suited for an IPR.
`
`For the reasons above, taken individually or based on a holistic assessment,
`
`the Board should grant Patent Owner’s request for discretionary denial.
`
`II. The ’151 Patent: A Lifeline for Breast Cancer Patients
`Breast cancer continues to be a formidable public health challenge, remaining
`
`as the most common form of cancer in women and second leading cause of cancer
`
`death in humans. See, e.g., EX1001, 1:18-20. Hormone-dependent breast cancer
`
`
`
`4
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`IPR2025-00799
`U.S. Patent 11,261,151
`represents the most prevalent subtype. EX2001, 18 (“ER+ breast cancer which
`
`comprises approximately…78% of all breast cancers.”). Tamoxifen has been a first-
`
`line treatment for hormone-dependent breast cancer, but many patients, due to
`
`genetic factors or drug interactions, cannot adequately metabolize tamoxifen into its
`
`active metabolite, endoxifen, rendering such treatment ineffective for those
`
`individuals. See EX1001, 1:61-2:38; 42:43-64. Tamoxifen is also known to have
`
`severe side effects. See id at 1:61-2:38. (Z)-endoxifen is the “main active metabolite
`
`responsible for the clinical efficacy of tamoxifen” and provides more consistent
`
`efficacy, regardless of patient genotype. See id.
`
`Obtaining relatively pure and stable forms of (Z)-endoxifen proved a
`
`challenge until the ’151 Patent. See id. at 27:23-40. The inventors of the ’151 Patent
`
`developed a novel synthesis process that avoids the inefficiencies and instabilities of
`
`prior methods, yielding a crystalized form of (Z)-endoxifen (at least 90% by weight)
`
`with superior stability and commercial-scale feasibility. See id.
`
`The ’151 Patent teaches a synthetic pathway and purification process to create
`
`this highly pure (Z)-endoxifen. EX1001 at Examples 1, 4-9. The starting isomeric
`
`mixture of (E)/(Z)-endoxifen is first subjected to crystallization. Id. Because the
`
`inventors observed that (E)-endoxifen is much less soluble than (Z)-endoxifen in a
`
`variety of solvents, this initial crystallization step results in an enriched (Z)-
`
`endoxifen component (e.g., a mother liquor or filtrate). See id. at 68:3-11 (“(Z)-
`
`
`
`5
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`IPR2025-00799
`U.S. Patent 11,261,151
`endoxifen was seen to be more soluble than (E)-endoxifen in EtOAc….Serial
`
`enrichment of Z-endoxifen by adding filtrates back to the first filtrate (first mother
`
`liquor) can also be performed.”). The enriched (Z)-endoxifen component is then
`
`subjected to further crystallization to obtain pure (Z)-endoxifen solid in a free base
`
`composition. See id. at 68:6-8 (“Both solids and filtrates are useful for the
`
`preparation of (Z)-endoxifen free base.”). The (Z)-endoxifen free-base solid
`
`composition obtained is shown to have increased stability in ambient conditions,
`
`with reduced isomeric conversion to the (E)-isomer. See id. at 84:20-28 (“Results
`
`show that solid Z-endoxifen free base is stable for at least 9 months at 5º C. and 25º
`
`C./60% RH…. (Z)-to-(E).
`
`The stable, highly-pure crystalline form of (Z)-endoxifen (“Form I”) claimed
`
`in the ’151 Patent aims to address the urgent need for a safer and more effective
`
`treatment and has improved bioavailability, bypassing metabolic limitations and
`
`providing consistent therapeutic benefit across diverse patient populations. Id. at
`
`1:61-2:53, 2:57-11:2, 98:28-100:45. Moreover, unlike existing synthetic methods,
`
`the process disclosed in the ’151 Patent to synthesize the claimed Form I with the
`
`claimed XPRD pattern achieves high yields, high purity, and improved stability, and
`
`is more economical and scalable for commercial production. Id. at 23:64-24:1,
`
`27:23-40, 30:8-35, 82:5-19. The claimed Form I with improved stability addresses,
`
`e.g., “a need for (Z)-endoxifen free base preparations that are sufficiently stable for
`
`
`
`6
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`IPR2025-00799
`U.S. Patent 11,261,151
`preparation of pharmaceutical compositions that are suitable for administering to
`
`subjects, for example, at ambient temperatures as well as at higher temperature and
`
`humidity.” See id. at 82:5-19. The invention described and claimed in the ‘151
`
`Patent is not merely an incremental improvement; it is a breakthrough innovation
`
`for breast cancer therapy.
`
`III. The Parties
`Patent Owner Atossa is a small clinical-stage American biopharmaceutical
`
`innovator with “small entity” status at the USPTO. See EX2001, 16; EX1002, 2,
`
`568. Atossa does not yet have any products on the market and therefore does not
`
`yet generate revenue sufficient to cover its operating costs. See EX2001, 6-7, 19
`
`(“We are in the research and development phase and are not currently marketing any
`
`products. We do not anticipate generating revenue unless and until we develop and
`
`launch our pharmaceutical programs.”). For the time being, Atossa depends on
`
`investments in the company to fund its research and clinical efforts (See EX2001,
`
`7)—as well as its defense of this dispute from Petitioner.
`
`Atossa’s business is focused on developing its claimed (Z)-endoxifen
`
`treatment to help patients with or at high risk for breast cancer. See EX2001, 7, 16;
`
`EX2010 (Atossa’s “focus remains firmly on advancing (Z)-endoxifen as a next-
`
`generation therapy for breast cancer patients across the full spectrum of care...”).
`
`Patent Owner is actively developing a free base form of (Z)-endoxifen and running
`
`
`
`7
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`IPR2025-00799
`U.S. Patent 11,261,151
`several Phase 2 clinical trials using a free base form of the claimed (Z)-endoxifen.
`
`See EX2001, 16-18. These trials include the EVANGELINE Trial, investigating it
`
`as a neoadjuvant treatment for premenopausal women; the I-SPY Trial, evaluating
`
`it in a Phase 2 sub-study for newly diagnosed ER+ invasive breast cancer; the
`
`RECAST-DCIS Study, assessing its suitability for neo-adjuvant endocrine therapy
`
`in women with Ductal Carcinoma In Situ; and the KARISMA Trial, demonstrating
`
`a statistically significant reduction in mammographic density, a major and under-
`
`addressed risk factor for breast cancer. See id.; EX2009. Additionally, Patent Owner
`
`is planning a Phase 3 trial, SMART 2.0, to investigate its potential in reducing
`
`interval breast cancer in high-risk women and is prioritizing its development for
`
`metastatic breast cancer. EX2002, 1.
`
`Petitioner Intas is a large foreign manufacturer of generic drugs with billions
`
`in annual revenue and significantly greater resources. EX2004, 1. Intas appears to
`
`have a relationship with Jina Pharmaceuticals Inc.,1 which Intas says “may be
`
`interested” in the outcome of this IPR (Pet.2), and which is currently involved in
`
`
`1 Though Jina is not listed as an RPI in the Petition, Intas and Jina appear to have a
`
`relationship related to endoxifen and the treatment of bipolar disorder (see, e.g.,
`
`EX2019, 1; EX2020)
`
`
`
`
`
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`8
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`IPR2025-00799
`U.S. Patent 11,261,151
`Phase 3 trials using (Z)-endoxifen (in a salt form) to treat for Bipolar I Disorder (see
`
`EX2006).
`
`IV. The Board May Take Into Account All Relevant Considerations in
`Exercising its Discretion to Deny Institution
`The Board has discretion to deny institution under 35 U.S.C. §§ 314(a) and
`
`325(d).2 Pursuant to the Office’s March 26, 2025 Guidance, the Board may look to
`
`“all relevant considerations” in exercising discretionary denial, including: “whether
`
`the PTAB or another forum has already adjudicated the validity or patentability of
`
`the challenged patent claims;” “the strength of the unpatentability challenge;” “the
`
`extent of the petition’s reliance on expert testimony;” “settled expectations of the
`
`parties, such as the length of time the claims have been in force;” “compelling
`
`economic, public health, or national security
`
`interests;” and “any other
`
`considerations bearing on the Director's discretion.” See March 26 Guidance at 2-3.
`
`Each of the considerations addressed below, both taken independently and assessed
`
`together, supports discretionary denial.
`
`A. Compelling Public Health Interests Support Discretionary Denial
`Public health considerations here favor discretionary denial. Atossa has the
`
`potential to substantially improve patient outcomes, as suggested by Patent Owner’s
`
`
`2 Unless stated, statutory and regulatory citations are to 35 U.S.C. or 37 C.F.R., as
`
`context indicates, internal citations omitted, and emphases/annotations are added.
`
`
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`9
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`IPR2025-00799
`U.S. Patent 11,261,151
`ongoing clinical trials using its (Z)-endoxifen. Early results have shown that the (Z)-
`
`endoxifen used by Atossa in its clinical trials “more than doubled the median
`
`[progression-free survival] compared to tamoxifen” in certain patients. See EX2003,
`
`1. Its tolerability is a critical advantage, as it can lead to better patient adherence
`
`and an enhanced quality of life, especially for those with incurable metastatic breast
`
`cancer. See id.
`
`Atossa’s clinical trial programs represent ongoing multi-year, multi-million-
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`dollar investments. See EX2013, 8 (listing “Research and development” at $14.1
`
`million for 2024 and $17.3 million for 2023). As a small innovative clinical-stage
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`biopharmaceutical company, Patent Owner depends on external investment to fund
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`these programs. See EX2001 at 6, 7, 16, 19. Atossa’s IP, including the ’151 Patent
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`and its patent family, helps Patent Owner build and maintain investor confidence,
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`enabling the continued funding of these critical trials. See id. at 4, 21, 24, 33-34;
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`EX2013, 8-9. Petitioner’s IPR undermines this confidence at a critical time of the
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`development of (Z)-endoxifen for breast cancer, which could lead to delays,
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`suspension, or even outright termination of ongoing and planned clinical trials,
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`directly impacting patient enrollment and access to investigational therapies, and
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`distracting management. See id. at 21 (“If we are unable to raise additional capital
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`when needed on reasonable terms, if at all, we could be forced to curtail or cease our
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`operations. Our future capital uses and requirements will depend on the time and
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`U.S. Patent 11,261,151
`expenses needed to begin and continue clinical trials for our new drug
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`developments.”), 34 (“Any litigation proceedings relating to our propriety
`
`technology… may result in substantial costs and distract our management and other
`
`employees”); EX2013, 8-9 (“Intellectual property is important to our business and
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`future income streams will depend, in part, on our ability to obtain and maintain
`
`patents”); EX2005 (“the ’151 Patent,’ with its estimated expiration in 2038,
`
`strengthens our intellectual property estate and should create long-term stockholder
`
`value”); see also EX2021 (“this new patent will create long-term stockholder value
`
`as it further validates and expands Atossa’s patent protection beyond our previously
`
`issued composition of matter patents”); infra §IV.(B) (providing covenant not to
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`sue); EX2008.3
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`Such disruption would not only harm Patent Owner but, more importantly,
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`would directly undermine public health by delaying or preventing access to a
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`promising new therapy for breast cancer—a disease with significant unmet medical
`
`
`3 This IPR is not an isolated challenge, but instead is the latest in a series of
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`coordinated attacks by Petitioner against Patent Owner’s intellectual property related
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`to (Z)-endoxifen. See Pet.2 (acknowledging prior “PGR2023-00043” and noting “at
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`the same time [Petitioner is] filing a petition for Post Grant Review challenging
`
`related U.S. Patent No. 12,071,391”).
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`needs. Individuals suffering from hormone-dependent breast cancer, especially
`
`those with metastatic or endocrine-resistant forms, eventually exhaust standard
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`and/or older therapies and depend on newer and novel options to extend survival.
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`Atossa is working to develop those options. The progression of their disease during
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`such delays may render them ineligible for future treatment or diminish the
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`effectiveness of any eventual therapy. The potential for increased progression-free
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`survival using Patent Owner’s (Z)-endoxifen also represents a significant quality of
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`life and economic benefit in reducing healthcare costs associated with more
`
`aggressive treatments.
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` See EX2012, 2; EX2001, 18 (“(Z)-endoxifen for
`
`Neoadjuvant Treatment of Breast Cancer. We are also developing (Z)-endoxifen to
`
`treat estrogen receptor positive (ER+) / human epidermal growth factor receptor 2
`
`negative (HER2-) breast cancer in the neoadjuvant setting, which is the
`
`administration of a therapy before the main treatment, which is usually surgery.”).
`
`And while Intas uses a salt form of (Z)-endoxifen in India to treat bipolar
`
`disorder (EX2019, EX2020), and Intas (with Jina) appears to be involved in clinical
`
`trials using (Z)-endoxifen only to treat bipolar disorder, Intas has nevertheless
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`chosen to include in its various PTAB challenges claims specifically limited to breast
`
`disorders—claims not implicated by their very different work. Pet.35-36
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`(challenging claim 16, “[a] method of treating a hormone-dependent breast
`
`disorder”), 36 (challenging claim 18, “wherein the subject has tamoxifen-refractory
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`or tamoxifen resistant hormone-dependent breast disorder”); see EX2017, 34-37
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`(challenging claims 42 (“treating a hormone-dependent breast disorder”), claim 43
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`(“wherein the hormone-dependent breast disorder… is… breast cancer”), claim 44
`
`(“wherein the hormone-dependent breast disorder… is tamoxifen-refractory or
`
`tamoxifen resistant”)); EX2018, 33-34 (challenging claim 20 (“treating a hormone-
`
`dependent breast disorder”), 34 (challenging claim 21 (“wherein the hormone-
`
`dependent breast disorder… is… breast cancer”)), 35 (challenging claim 22
`
`(“wherein the hormone-dependent breast disorder… is tamoxifen-refractory or
`
`tamoxifen resistant.”)). Intas’s goal is seemingly to interfere with Atossa’s clinical
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`development of a treatment for breast cancer to the detriment of public health. See
`
`also §IV(B).
`
`The threat posed by Petitioner’s IPR is not just to Patent Owner’s patent rights
`
`and clinical development, but to the patients who stand to benefit from a safer, more
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`reliable breast cancer treatment. That potential harm to Patent Owner outweighs any
`
`arguable benefit to Petitioner in instituting this petition, particularly in view of Patent
`
`Owner’s stipulation discussed below, which leaves Intas and Jina free to pursue the
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`use of (Z)-endoxifen salts for the treatment of bipolar disorders, consistent with their
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`current trial.
`
`The USPTO’s recent guidance on its process for addressing discretionary
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`denial explicitly identifies “compelling economic, public health, or national security
`
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`interests” as a factor to be considered. See March 26 Guidance at 2. Given the
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`critical unmet needs in breast cancer, the unique advantages of the claimed (Z)-
`
`endoxifen for treating breast cancer, Patent Owner’s limited resources, and the
`
`advanced stage of Patent Owner’s clinical development, the public health interest in
`
`ensuring the uninterrupted progress of this therapy is strong. Allowing institution
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`here would not serve the goals of innovation or fairness; instead, it would enable a
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`large foreign generic to exploit the machinery of the AIA to derail a small American
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`innovator’s efforts to bring a potentially-critical breast cancer treatment to market.
`
`B.
`
`This Proceeding Would Waste the Board’s Resources Given Patent
`Owner’s Stipulation Not to Sue for Infringement
`As explained abo