US 10596162

US Patent 10,596,162, titled "Method for treating gefitinib resistant cancer," was granted to Wyeth LLC and General Hospital Corp.

Summary of US Patent 10,596,162:

• Title: Method for treating gefitinib resistant cancer
• Assignee: Wyeth LLC, General Hospital Corp
• Inventors: Daniel A. Haber, Daphne Winifred Bell, Jeffrey E. Settleman, Raffaella Sordella, Nadia G. Godin-Heymann, Eunice L. Kwak, Sridhar Krishna Rabindran
• Filing Date: July 11, 2016 (for application Ser. No. 15/207,349, from which this patent issued). The earliest priority date for this patent is February 3, 2005.
• Issue Date: March 24, 2020
• Abstract: The patent describes methods for treating cancer that has become resistant to gefitinib and/or erlotinib. The method involves monitoring a patient's cancer progression after they have started gefitinib or erlotinib treatment. If the cancer progresses, indicating resistance, the patient is then given a pharmaceutical composition containing an irreversible epidermal growth factor receptor (EGFR) inhibitor. Preferred irreversible EGFR inhibitors mentioned include EKB-569, HKI-272, and HKI-357.

Plain-Language Overview of Independent Claims:

The patent contains two independent claims, Claim 1 and Claim 9.

• Claim 1: This claim describes a method for treating cancer that has become resistant to gefitinib and/or erlotinib in a patient. The method involves two main steps:

  1. Monitoring: The patient's cancer progression is monitored after they have begun treatment with gefitinib and/or erlotinib. If the cancer progresses, it means the cancer is resistant to these initial treatments.
  2. Administering: Once cancer progression (resistance) is observed, the patient is given a drug that is an irreversible epidermal growth factor receptor (EGFR) inhibitor.

• Claim 9: This claim describes a method for treating cancer in a patient who has a specific genetic mutation in their EGFR. This mutation is a change where a threonine (T) at position 790 is replaced by a methionine (M) (known as T790M) in the EGFR protein (SEQ ID NO: 1). This T790M mutation is known to cause resistance to gefitinib and/or erlotinib. The method involves administering to this patient a pharmaceutical composition that contains an irreversible EGFR inhibitor.

Litigation Status:

US Patent 10,596,162 has been involved in litigation. On July 9, 2026, in the case of Wyeth LLC v. AstraZeneca Pharmaceuticals LP, No. 2024-2325, the Court of Appeals for the Federal Circuit (CAFC) affirmed a district court's ruling that found certain asserted claims of this patent (and US10603314) invalid for lack of enablement under 35 U.S.C. § 112(a). The core issue was that the patent's specification did not adequately teach a skilled artisan how to determine a therapeutically effective daily unit dosage for the claimed compounds without requiring undue experimentation.

Known Litigation Involving US Patent 10,596,162

As of 2026-07-10, US Patent 10,596,162 has been involved in at least one significant litigation case:

• Case Name: Wyeth LLC v. AstraZeneca Pharmaceuticals LP
• Plaintiff(s): Wyeth LLC (a Pfizer subsidiary)
• Defendant(s): AstraZeneca Pharmaceuticals LP
• Jurisdiction: U.S. Court of Appeals for the Federal Circuit
• Case Number: No. 24-2325
• Filing Dates: Pfizer (on behalf of Wyeth) initially sued AstraZeneca in 2021. The appeal to the Federal Circuit (No. 24-2325) was filed in 2024.
• Outcome/Current Status: On July 9, 2026, the U.S. Court of Appeals for the Federal Circuit affirmed a district court's ruling, finding certain asserted claims of US Patent 10,596,162 (and US Patent 10,603,314) invalid for lack of enablement under 35 U.S.C. § 112(a). This decision upheld a district court's judgment as a matter of law, which had overturned a $107.5 million jury verdict previously won by Wyeth against AstraZeneca in Delaware in 2024. The Federal Circuit's unanimous panel agreed that the patent specification did not adequately teach a skilled artisan how to determine a therapeutically effective daily unit dosage for the claimed compounds without undue experimentation.

Proceedings overview

There are no AIA trial proceedings (Inter Partes Review, Post-Grant Review, or Covered Business Method review) on file for US Patent 10596162 with the USPTO as of the most recent ingest, nor have web searches surfaced any such proceedings. This means that from a PTAB perspective, the patent's claims have not been challenged or adjudicated through these specific administrative trial processes.

Strategic summary

As there are no PTAB proceedings associated with US10596162, all claims of the patent (Claims 1-9) remain untested by the AIA trial process. This implies there is no PTAB-specific estoppel landscape to consider.

However, it is critical to note the separate, significant development from the Federal Circuit. On July 9, 2026, in Wyeth LLC v. AstraZeneca Pharmaceuticals LP, No. 2024-2325, the Court of Appeals for the Federal Circuit (CAFC) affirmed a district court's ruling that found certain asserted claims of US10596162 (and US10603314) invalid for lack of enablement under 35 U.S.C. § 112(a). This decision, while not originating from the PTAB, has a direct impact on the enforceability of the patent's claims. The specific claims deemed invalid by the district court and affirmed by the CAFC are not detailed in the provided context, but their invalidation under § 112(a) is a critical defensive point.

Recommended next steps

Given the absence of PTAB proceedings, the focus for any defendant facing assertion of US10596162 should immediately shift to the recent Federal Circuit decision.

• Obtain the CAFC opinion and underlying District Court judgment: Identify which specific claims of US10596162 were found invalid for lack of enablement under 35 U.S.C. § 112(a) in Wyeth LLC v. AstraZeneca Pharmaceuticals LP, No. 2024-2325. The Federal Circuit's opinion can be accessed via CourtListener or the CAFC's docket. This is crucial for determining which claims are no longer assertable.
• Analyze the scope of invalidity: Understand whether the invalidated claims are independent or dependent, and how this impacts potential infringement theories. If the demand letter cites claims that have been ruled invalid, the asserting party's case for those claims is significantly weakened or non-existent.
• Consider defensive options beyond PTAB: Since PTAB has not been utilized for this patent, and the Federal Circuit has already affirmed invalidity on § 112(a) grounds for some claims, any new challenge might focus on other patentability grounds (e.g., § 102/103 prior art) in district court or explore the full implications of the enablement ruling for any remaining asserted claims.

Inventors

• Daniel A. Haber: The General Hospital Corporation
• Daphne Winifred Bell: The General Hospital Corporation
• Jeffrey E. Settleman: The General Hospital Corporation
• Raffaella Sordella: The General Hospital Corporation
• Nadia G. Godin-Heymann: The General Hospital Corporation
• Eunice L. Kwak: The General Hospital Corporation
• Sridhar Krishna Rabindran: Wyeth LLC

(Employer affiliations determined by the assignments recorded on 2019-10-28, where individual inventors assigned their interests to the respective entities.)

Original assignee

The entities named on the issued patent (and the original assignees as indicated by the initial assignments from inventors) are Wyeth LLC and The General Hospital Corporation.

• Wyeth LLC: A major pharmaceutical company. Wyeth developed several of the compounds mentioned in the patent, such as EKB-569, HKI-272, and HKI-357. These compounds relate directly to the claims for treating gefitinib-resistant cancer. Wyeth was acquired by Pfizer Inc. in 2009.
• The General Hospital Corporation: Operates Massachusetts General Hospital, a major academic medical center. Its primary business is healthcare, medical research, and education. It is an operating entity.

Assignment timeline

The USPTO Assignment Center search results for patent number 10596162 (https://assignmentcenter.uspto.gov/patent/10596162) show the following assignment records:

• 2005-11-23 (executed) / recorded 2005-12-07 — Reel 016709/0816
  • Conveyance: Assignment of Assignors Interest
  • Assignor: Sordella, Raffaella; Settleman, Jeffrey E.; Haber, Daniel A.; Bell, Daphne Winifred; Godin-Heymann, Nadia G.; Kwak, Eunice L.
  • Assignee: The General Hospital Corporation
  • Correspondent: FISH & RICHARDSON P.C., P.O. BOX 1022, MINNEAPOLIS, MN 55440-1022
  • Context: Transfer of inventors' rights to their employer, The General Hospital Corporation.
• 2005-11-28 (executed) / recorded 2005-12-07 — Reel 016709/0833
  • Conveyance: Assignment of Assignors Interest
  • Assignor: Rabindran, Sridhar Krishna
  • Assignee: Wyeth
  • Correspondent: WYETH, FIVE GIRALDA FARMS, MADISON, NJ 07940
  • Context: Transfer of inventor's rights to their employer, Wyeth.
• 2009-10-15 (executed) / recorded 2010-02-09 — Reel 024109/0677
  • Conveyance: Merger
  • Assignor: Wyeth (formerly known as American Home Products Corporation)
  • Assignee: Pfizer Inc.
  • Correspondent: PFIZER INC., 201 TABOR ROAD, MORRIS PLAINS, NJ 07950
  • Context: Acquisition of Wyeth by Pfizer Inc.
• 2019-10-28 (executed) / recorded 2019-10-28 — Reel 048740/0173
  • Conveyance: Assignment of Assignors Interest (Correction)
  • Assignor: Kwak, Eunice L.; Sordella, Raffaella; Settleman, Jeffrey E.; Haber, Daniel A.; Godin-Heymann, Nadia G.; Bell, Daphne Winifred
  • Assignee: THE GENERAL HOSPITAL CORPORATION
  • Correspondent: FISH & RICHARDSON P.C., P.O. BOX 1022, MINNEAPOLIS, MN 55440-1022. This correspondent firm also handled the original inventor assignment to The General Hospital Corporation.
  • Context: Corrective assignment from inventors to The General Hospital Corporation.
• 2019-10-28 (executed) / recorded 2019-10-28 — Reel 048740/0179
  • Conveyance: Assignment of Assignors Interest (Correction)
  • Assignor: RABINDRAN, SRIDHAR KRISHNA
  • Assignee: WYETH
  • Correspondent: PFIZER INC., 235 EAST 42ND STREET, NEW YORK, NY 10017
  • Context: Corrective assignment from inventor to Wyeth.
• 2019-10-28 (executed) / recorded 2019-10-28 — Reel 048740/0187
  • Conveyance: Change of Name
  • Assignor: WYETH
  • Assignee: WYETH LLC
  • Correspondent: PFIZER INC., 235 EAST 42ND STREET, NEW YORK, NY 10017
  • Context: Formal change of name for Wyeth entity, likely reflecting internal corporate structure post-Pfizer acquisition.
• 2020-02-27 (executed) / recorded 2020-03-09 — Reel 049581/0890
  • Conveyance: Assignment
  • Assignor: Pfizer Inc.
  • Assignee: Wyeth LLC
  • Correspondent: PFIZER INC., 235 EAST 42ND STREET, NEW YORK, NY 10017. This correspondent also handled previous Pfizer/Wyeth related assignments.
  • Context: Transfer from Pfizer Inc. back to its subsidiary, Wyeth LLC, likely an internal corporate reorganization within Pfizer.

Timeline diagram

timeline
    title Ownership of US 10596162
    2005 : Inventors assign to General Hospital Corp and Wyeth
    2009 : Wyeth acquired by Pfizer Inc
    2019 : Corrective assignments to General Hospital Corp and Wyeth
         : Wyeth changes name to Wyeth LLC
    2020 : Pfizer Inc assigns to Wyeth LLC

NPE / troll-pattern signals

1. Shell-entity transfer — Not present. The assignees in the chain (The General Hospital Corporation, Wyeth, Pfizer Inc., Wyeth LLC) are all established operating companies.
2. Known asserter in the chain — Not present. None of the entities in the assignment chain (The General Hospital Corporation, Wyeth, Pfizer Inc., Wyeth LLC) are recognized as known NPEs or patent trolls.
3. Repeat correspondent across the chain — Present.
   • FISH & RICHARDSON P.C. appears on Reel 016709/0816 (2005) and Reel 048740/0173 (2019). This firm handled both the initial and corrective assignments for The General Hospital Corporation.
   • PFIZER INC. (or its internal legal department) appears as the correspondent on Reel 024109/0677 (2010), Reel 048740/0179 (2019), Reel 048740/0187 (2019), and Reel 049581/0890 (2020). This indicates consistent internal handling of assignments post-acquisition.
4. Cascading transfers — Not present. The transfers are spaced out over years and primarily reflect corporate acquisitions or internal reorganizations, not rapid transfers between shell entities.
5. Pre-litigation transfer — Unclear. The patent's first litigation (Wyeth LLC v. AstraZeneca Pharmaceuticals LP, No. 2024-2325) was filed in 2024. The last recorded assignment was in March 2020 (Reel 049581/0890), which is more than 6 months prior to the litigation. However, the litigation is by Wyeth LLC (which is now Pfizer's subsidiary), an operating company.
6. Bankruptcy fire-sale — Not present. Wyeth was acquired by Pfizer, which was a strategic acquisition, not a bankruptcy sale.
7. Privateering — Unclear. While Wyeth LLC (a Pfizer subsidiary) is asserting the patent, it is unclear if this is considered "privateering" as typically defined (an operating company transferring to an NPE for assertion). Here, the assertion is by the operating company's subsidiary, which is a common corporate practice.
8. Defensive aggregator (anti-NPE) — Not present. The patent is not currently held by a defensive aggregator.

Verdict

Operating-company assertion

The patent ownership chain primarily reflects standard corporate activities, including initial assignments from inventors to their employers (The General Hospital Corporation and Wyeth), followed by the acquisition of Wyeth by Pfizer Inc. Subsequent assignments involve internal reorganizations within Pfizer, where Wyeth LLC acts as a subsidiary. The litigation is being pursued by Wyeth LLC against a competitor (AstraZeneca Pharmaceuticals LP), which is characteristic of an operating company asserting its intellectual property.

USPTO Assignment Center: https://assignmentcenter.uspto.gov/patent/10596162

To identify the most relevant prior art for US patent 10,596,162, I will examine the patent citations listed in the Google Patents entry for US10596162B2. The patent states it has 187 patent citations and 657 non-patent citations. I will focus on the patent citations provided to give a representative sample of the prior art.

Please note that a comprehensive analysis of all 187 patent citations and 657 non-patent citations is beyond the scope of this response due to the extensive number of references. I will highlight a few examples that appear to be highly relevant based on their titles and common themes with US 10,596,162.

Publication and Filing Dates of US 10,596,162:

• Earliest Priority Date: February 3, 2005.
• Filing Date (for application Ser. No. 15/207,349): July 11, 2016.
• Issue Date: March 24, 2020.

The claims of US 10,596,162 relate to methods of treating gefitinib and/or erlotinib resistant cancer using irreversible EGFR inhibitors, especially in cases with the T790M mutation or altered EGFR trafficking. The prior art references are examined for disclosures that might anticipate these methods, particularly regarding the use of irreversible EGFR inhibitors for resistant cancers, the T790M mutation, or the general concept of monitoring resistance and switching therapies.

Here are some examples of potentially relevant prior art patents cited by US 10,596,162:

• US6002008A

  • Full Citation: US6002008A
  • Publication/Filing Date: Publication date: 1999-12-14. Priority dates range from 1996-03-29.
  • Brief Description: This patent is broadly titled "Quinoxaline Derivatives". While the specific claims are not fully detailed here, a patent with this title could disclose compounds that act as kinase inhibitors, potentially including irreversible EGFR inhibitors. Given that EKB-569, HKI-272, and HKI-357 are mentioned as 4-anilinoquinoline-3-carbonitrile derivatives, which are quinazoline derivatives, this patent might describe similar chemical structures or their use in cancer treatment, which could be relevant to the irreversible EGFR inhibitors claimed in US10596162.
  • Potential Anticipation: Depending on the specific compounds and their disclosed therapeutic uses, this patent could potentially anticipate aspects of claims related to the irreversible EGFR inhibitors themselves, or the general concept of using such compounds for cancer treatment. Specifically, if it discloses irreversible EGFR inhibitors, it could potentially anticipate the administration step in claims 1 and 9, if those compounds are effective against gefitinib/erlotinib resistance.

• WO0018761A1

  • Full Citation: WO0018761A1
  • Publication/Filing Date: Publication date: 2000-04-06. Priority dates range from 1998-09-29.
  • Brief Description: Titled "2-Anilino-pyrimidine derivatives as protein tyrosine kinase inhibitors", this patent covers a class of compounds that inhibit protein tyrosine kinases. EGFR is a protein tyrosine kinase, and its inhibition is central to US 10,596,162. This reference could disclose compounds with similar mechanisms of action to the irreversible EGFR inhibitors.
  • Potential Anticipation: This could potentially anticipate the use of specific tyrosine kinase inhibitors for cancer treatment, particularly if any of the disclosed compounds are irreversible EGFR inhibitors with efficacy against resistant forms of cancer, thus potentially anticipating the core concept of claims 1 and 9.

• WO0123395A2

  • Full Citation: WO0123395A2
  • Publication/Filing Date: Publication date: 2001-04-05. Priority dates range from 1999-09-24.
  • Brief Description: This patent is titled "Pyridopyrimidine compounds for use as tyrosine kinase inhibitors". Similar to the previous example, this patent describes another class of tyrosine kinase inhibitors. Given that EGFR-TKIs include quinazolines, pyridopyrimidines, and pyrrolopyrimidines, this reference is highly relevant to the class of compounds discussed in US 10,596,162.
  • Potential Anticipation: If this patent discloses specific pyridopyrimidine compounds that are irreversible EGFR inhibitors and discusses their utility in resistant cancers, it could potentially anticipate the administration steps of claims 1 and 9.

• US2002002162A1

  • Full Citation: US2002002162A1
  • Publication/Filing Date: Publication date: 2002-01-03. Priority dates range from 2000-05-18.
  • Brief Description: Titled "Method for treating hyperproliferative disorders", this patent may describe methods for treating cancer and other conditions characterized by abnormal cell growth. This could cover the general concept of treating cancer, and depending on the specific agents and patient selection criteria, could potentially be relevant to the treatment methods in US 10,596,162.
  • Potential Anticipation: If this reference details the use of specific EGFR inhibitors (especially irreversible ones) for hyperproliferative disorders, particularly in the context of drug resistance or specific mutations, it could anticipate elements of claims 1 and 9.

It is crucial to note that "potential anticipation" under 35 U.S.C. § 102 requires that all elements of a claim be present, either explicitly or inherently, in a single prior art reference. A thorough analysis would involve a detailed comparison of each claim element against the full text of each cited prior art document. The provided descriptions are based on titles and general summaries, which are insufficient for a definitive legal determination of anticipation. Furthermore, the litigation status indicates that claims were found invalid for lack of enablement, not necessarily for anticipation by these specific prior art patents.

Obviousness Analysis of US Patent 10,596,162 Under 35 U.S.C. § 103

This analysis assesses the obviousness of claims 1 and 9 of US Patent 10,596,162, considering prior art available before the patent's earliest priority date of February 3, 2005. A patent claim is considered obvious 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 (POSA). This requires identifying a motivation to combine prior art references with a reasonable expectation of success.

Claim 1 Obviousness Analysis

Claim 1: A method for treating gefitinib and/or erlotinib resistant cancer in a subject, comprising:
monitoring progression of cancer in the subject at a time point after the subject has initiated gefitinib and/or erlotinib treatment, wherein progression of the cancer is indicative of cancer that is resistant to gefitinib and/or erlotinib treatment; and
administering to the subject a pharmaceutical composition comprising an irreversible epidermal growth factor receptor (EGFR) inhibitor.

Elements of Claim 1:

1. Monitoring progression of cancer in the subject after gefitinib/erlotinib treatment, where progression indicates resistance: The patent itself describes this as a known method for diagnosing resistance. For example, the patent states, "Diagnosis of gefitinib and/or erlotinib resistance may be accomplished by way of monitoring tumor progression during gefitinib and/or erlotinib treatment." and "Progression of the cancer during treatment with gefitinib and/or erlotinib indicates gefitinib and/or erlotinib resistance." (US10596162B2, Description, "Method of Treating a Patient" section). Monitoring cancer progression (e.g., via visual inspection like X-ray, CT scan, or MRI, or by tumor biomarker detection) is a fundamental and well-established clinical practice in oncology to assess treatment efficacy and detect drug resistance.
2. Administering to the subject a pharmaceutical composition comprising an irreversible epidermal growth factor receptor (EGFR) inhibitor:
   • Problem: The patent explicitly identifies the problem of gefitinib and/or erlotinib resistance in cancer treatment, stating, "A significant limitation in using these compounds is that recipients thereof may develop a resistance to their therapeutic effects after they initially respond to therapy, or they may not respond to EGFR-TKIs to any measurable degree at all." (US10596162B2, Background).
   • Known Irreversible EGFR Inhibitors: Prior to February 3, 2005, several irreversible EGFR inhibitors were known in the art. For example:
     • EKB-569: Was described in Greenberger et al., 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy, Amsterdam, Nov. 7-10, 2000, abstract 388. The patent text confirms, "EKB-569 (4-anilinoquinoline-3-carbonitrile; Greenberger et al., 11 th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy, Amsterdam, Nov. 7-10, 2000, abstract 388; Wyeth)" (US10596162B2, Description, "Method of Treating a Patient" section).
     • HKI-272: Was described in Rabindran et al., Cancer Res. 2004, 64, 3958-3965. The patent refers to "HKI-272 (a derivative of 4-anilinoquinoline-3-carbonitrile; Rabindran et al., Cancer Res. 2004, 64, 3958-3965; Wyeth)" (US10596162B2, Description, "Method of Treating a Patient" section).
   • Known Efficacy Against Resistance (specifically T790M): The patent itself acknowledges the emerging knowledge regarding the efficacy of irreversible EGFR inhibitors against resistant mutations: "While this work was in progress, another irreversible inhibitor of EGFR [CL-387,785, Calbiochem (27)] was shown to inhibit the kinase activity of the T790M EGFR mutant (17)." (US10596162B2, Description, "Results and Discussion" section). Reference (17) is Pao et al., Science 2005, which was accepted for publication on February 2, 2005, one day before the priority date of US10596162. This indicates that the effectiveness of an irreversible EGFR inhibitor against a gefitinib/erlotinib resistance-conferring mutation (T790M) was known or publicly available just before the priority date.

Motivation to Combine:
A person having ordinary skill in the art (POSA) in oncology or pharmaceutical development, faced with the known problem of gefitinib/erlotinib resistance, would have a strong motivation to explore alternative treatments. Knowing that reversible EGFR inhibitors like gefitinib and erlotinib act by competing for the ATP binding site, and observing the development of resistance (which could be due to mutations affecting binding or other mechanisms), a POSA would naturally look for agents with a different mechanism of action. Irreversible EGFR inhibitors, which form a covalent bond with the receptor (e.g., at Cys773 of EGFR as mentioned in the patent), represent such a distinct mechanism. The analogy to imatinib resistance in CML, where secondary mutations led to drug resistance and the search for new inhibitors, would also motivate a POSA to consider different classes of kinase inhibitors.

Crucially, the knowledge that at least one irreversible EGFR inhibitor (CL-387,785) was already shown to be effective against the T790M mutation (a known resistance mechanism) provided a strong basis and expectation of success for using other known irreversible EGFR inhibitors (like EKB-569 or HKI-272) to treat gefitinib/erlotinib resistant cancers more generally. The decision to switch to a known irreversible EGFR inhibitor upon observing resistance would be an obvious clinical step for a POSA seeking to overcome treatment failure.

Claim 9 Obviousness Analysis

Claim 9: A method of treating cancer, comprising administering to a subject having a mutation in EGFR, namely, a substitution of a methionine for a threonine at position 790 (T790M) of SEQ ID. No. 1, a pharmaceutical composition comprising an irreversible EGFR inhibitor. The T790M mutation confers resistance to gefitinib and/or erlotinib treatment.

Elements of Claim 9:

1. Subject having a T790M mutation in EGFR (SEQ ID NO: 1), which confers resistance to gefitinib and/or erlotinib treatment:

   • The identification of the T790M mutation as a key mechanism of acquired resistance to gefitinib and erlotinib was publicly disclosed prior to the priority date of this patent.
   • Pao et al., Science 2005 (Ref. 17): This paper was accepted for publication on February 2, 2005, one day prior to the priority date of US10596162. It describes the T790M mutation in EGFR as a secondary mutation that mediates acquired resistance to gefitinib and erlotinib in non-small cell lung cancer.
   • Kobayashi et al., N Engl J Med. 2005 Feb 24;352(8):786-92: This paper, published on February 24, 2005, explicitly states: "The DNA sequence of the EGFR gene in his tumor biopsy specimen at relapse revealed the presence of a second point mutation, resulting in threonine-to-methionine amino acid change at position 790 of EGFR. Structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance.". While published after the priority date, the proximity in time suggests the underlying research and findings were emerging knowledge for a POSA. The patent itself identifies this as prior art or contemporaneously discovered information (via reference 18, which is a related Kobayashi paper with a slightly later publication date).
   • Therefore, the knowledge that the T790M mutation in EGFR confers resistance to gefitinib and/or erlotinib was known or readily ascertainable by a POSA at the time of the invention.

2. Administering to the subject a pharmaceutical composition comprising an irreversible EGFR inhibitor:

   • As discussed for Claim 1, irreversible EGFR inhibitors such as EKB-569 (Greenberger et al., 2000) and HKI-272 (Rabindran et al., 2004) were known compounds prior to the priority date.
   • Crucially, Pao et al. (17) also explicitly demonstrated that an irreversible EGFR inhibitor, CL-387,785, was capable of inhibiting the kinase activity of the T790M EGFR mutant. The patent confirms this, stating, "While this work was in progress, another irreversible inhibitor of EGFR [CL-387,785, Calbiochem (27)] was shown to inhibit the kinase activity of the T790M EGFR mutant (17)." (US10596162B2, Description, "Results and Discussion" section).

Motivation to Combine:
A POSA, having knowledge from Pao et al. (17) that the T790M mutation leads to gefitinib/erlotinib resistance and that an irreversible EGFR inhibitor (CL-387,785) is effective against this mutant, would have a clear and strong motivation to administer any known irreversible EGFR inhibitor to a patient diagnosed with T790M mutant cancer. The common mechanism of action for irreversible EGFR inhibitors (covalent binding to Cys773) would lead a POSA to reasonably expect that other known irreversible inhibitors, such as EKB-569 and HKI-272, would also be effective against the T790M mutant, similar to CL-387,785. Therefore, substituting one known irreversible EGFR inhibitor for another, in a context where an irreversible inhibitor was already shown to work for the specific mutation, would be obvious to a POSA.

Conclusion on Obviousness

Both independent claims 1 and 9 appear to be obvious in light of the identified prior art. The problem of gefitinib/erlotinib resistance was well-known, as were various irreversible EGFR inhibitors. The crucial element connecting these, the efficacy of an irreversible EGFR inhibitor against the T790M resistance mutation, was disclosed in Pao et al. (17), which was accepted for publication before the priority date. This information, combined with general medical practice and the motivation to explore alternative drug classes for resistant cancers, would lead a POSA to the claimed methods with a reasonable expectation of success.