Obviousness

Obviousness Analysis under 35 U.S.C. § 103 for US Patent 10980901

This analysis evaluates the obviousness of US Patent 10980901 under 35 U.S.C. § 103, based on the provided prior art references and focusing on independent claim 1. A claim is 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). The priority date for US 10980901 is December 15, 2016.

Independent Claim 1 Summary:

Independent Claim 1 describes a method for treating PSMA-expressing cancers by administering an effective amount of one or more Ac-225-radiopharmaceuticals. These radiopharmaceuticals comprise Ac-225 chelated with a targeting compound selected from Formula (A), (B), (C), (D), or (E). The effective amount is administered as a dosage of from 25 kBq/kg to 400 kBq/kg of body weight, or as a unitary dosage of from 3 MBq to 30 MBq.

Key Elements of Independent Claim 1 and Prior Art Disclosures:

1. Method for treating PSMA expressing cancers:

   • Kratochwil, Clemens et al., "225 Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer", The Journal of Nuclear Medicine, Jul. 7, 2016 (hereinafter "Kratochwil 2016") explicitly teaches "PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer". Prostate cancer is a known PSMA-expressing cancer.
   • Afshar-Oromieh, Ali et al., "The Rise of PSMA Ligands for Diagnosis and Therapy of Prostate Cancer", The Journal of Nuclear Medicine, Oct. 2016, discusses PSMA ligands for the therapy of prostate cancer.
   • The teachings of US Patent 10398791B2 (published as US20140112879A1 on April 24, 2014) and US Patent 10471160B2 (published as US20140112880A1 on April 24, 2014), both titled "Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer," clearly disclose treating prostate cancer using PSMA-targeting agents.
   • Sathekge, Mike et al., "68Ga-PSMA-HBED-CC PET imaging in breast carcinoma patients", European Journal of Nuclear Medicine and Molecular Imaging, Nov. 8, 2016, indicates that PSMA is expressed in breast carcinoma and can be targeted.

2. Administering one or more Ac-225-radiopharmaceuticals:

   • Kratochwil 2016 directly discloses the administration of "225Ac-PSMA-617" for therapy.
   • Hadaschik Boris, "Re:225Ac-PSMA-617 for PSMA-Targeting Alpharadiation Therapy of Patients with Metastatic Castration-resistant Prostate Cancer", European Urology, Aug. 21, 2016, also discusses 225Ac-PSMA-617 therapy.
   • Apostolidis Christos, et al., "Production of Ac-225 from Th-229 for targeted alpha therapy", Analytical Chemistry, 2005, and Zielinska B. et al., "An Improved Method for the Production of Ac225/Bi-213 from Th-229 for Targeted Alpha Therapy", Solvent Extraction and Ion Exchange, 2007, establish that Ac-225 was a known radionuclide for targeted alpha therapy.

3. Ac-225 chelated with a targeting compound of Formula (A), (B), (C), (D) or (E):

   • Kratochwil 2016 explicitly details the use of "225Ac-PSMA-617". PSMA-617 is a known PSMA-targeting ligand that incorporates a DOTA chelator, and the patent's description confirms Ac-225-PSMA-617 as "chelating a Ac-225 radionuclide with its 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid moiety" (DOTA). DOTA is listed as a chelator in Claim 1. This directly discloses an Ac-225-radiopharmaceutical comprising Ac-225 chelated with a specific targeting compound (PSMA-617), which falls within the scope of the claimed formulas.
   • US Patent 8926944B2 (Molecular Insight Pharmaceuticals), "Radiolabeled prostate specific membrane antigen inhibitors", published January 6, 2015, describes various radiolabeled PSMA binding ligands (targeting compounds). The teachings of US20140112879A1 and US20140112880A1 also disclose labeled PSMA inhibitors, encompassing a range of targeting moieties.

4. Specific dosage ranges (25-400 kBq/kg or 3-30 MBq):

   • Kratochwil 2016 explicitly states the administration of "Single doses of 100 kBq/kg body weight of 225Ac-PSMA-617". This dosage of 100 kBq/kg falls directly within the claimed range of 25 kBq/kg to 400 kBq/kg.
   • Kratochwil, Clemens et al., "Ac-225-DOTATOC—an empiric dose finding for alpha particle emitter based radionuclide therapy of neuroendocrine tumors", The Journal of Nuclear Medicine, May 1, 2015, demonstrates the known practice of "empiric dose finding for alpha particle emitter based radionuclide therapy".

Combination of Prior Art and Motivation to Combine:

A strong argument for obviousness of independent Claim 1 can be made by combining the teachings of Kratochwil 2016 as the primary reference, supplemented by Kratochwil, Clemens et al. (May 2015), and further informed by US Patent 8926944B2 and the teachings of US20140112879A1 and US20140112880A1.

1. Primary Disclosure (Kratochwil 2016): Kratochwil 2016 directly discloses treating PSMA-expressing metastatic castration-resistant prostate cancer with the Ac-225-radiopharmaceutical 225Ac-PSMA-617, administered at a dosage of 100 kBq/kg body weight. This reference alone anticipates or renders obvious nearly all elements of Claim 1, including the cancer type, the specific Ac-225 radiopharmaceutical (Ac-225 chelated with PSMA-617, a DOTA-conjugated targeting compound within the claimed scope), and a dosage within the claimed range.

2. Motivation for Dosage Ranges (Kratochwil 2015): Given the documented efficacy of 100 kBq/kg of Ac-225-PSMA-617 in Kratochwil 2016, a person having ordinary skill in the art (POSA) would have been motivated to optimize the dosage. Kratochwil (May 2015) demonstrates that "empiric dose finding for alpha particle emitter based radionuclide therapy" was a known and routine practice for Ac-225 radiopharmaceuticals in other cancer types. Therefore, a POSA would have found it obvious to explore variations around the established 100 kBq/kg dose, leading to the broader claimed ranges of 25-400 kBq/kg or 3-30 MBq (the latter being readily derivable from the former using typical patient weights). This exploration would be driven by a desire to find optimal therapeutic windows for different patients or disease stages, with a reasonable expectation of success.

3. Motivation for Broadening Targeting Compounds (US8926944B2, US20140112879A1, US20140112880A1): The prior art, including US8926944B2 and the teachings of US20140112879A1 and US20140112880A1, clearly disclosed various "radiolabeled prostate specific membrane antigen inhibitors" or "PSMA binding ligands" for therapeutic and diagnostic purposes. A POSA, observing the success of Ac-225-PSMA-617 (Kratochwil 2016), would have been motivated to combine the known potent alpha-emitter Ac-225 with other known PSMA-targeting compounds, such as those falling under general Formulas (A)-(E) described in Claim 1. This would be a routine substitution or optimization, driven by the goal of finding other effective PSMA-targeted radiopharmaceuticals. The general concept of conjugating radionuclides to targeting compounds via chelators (many of which are listed in Claim 1 and were well-known) was also well-established.

4. Motivation for Applying to Other PSMA-Expressing Cancers (Sathekge 2016): Given that PSMA expression was known in other cancer types beyond prostate cancer, such as breast cancer (Sathekge 2016), a POSA would have been motivated to apply successful PSMA-targeted therapies, such as Ac-225-radiopharmaceuticals, to these other PSMA-expressing malignancies. Extending the use of an effective targeted therapy to other diseases expressing the same target is a logical next step with a high likelihood of success.

In summary, the specific method of treating PSMA-expressing prostate cancer with Ac-225-PSMA-617 at a dosage of 100 kBq/kg was explicitly taught by Kratochwil 2016. Expanding the dosage range to encompass 25-400 kBq/kg or 3-30 MBq would have been obvious to a POSA engaging in routine dose optimization, a practice known in the field for Ac-225 radiopharmaceuticals (Kratochwil 2015). Furthermore, applying Ac-225 to other known PSMA-targeting compounds (like those in Formulas A-E) and to other PSMA-expressing cancers (e.g., breast cancer, Sathekge 2016), would have been obvious given the broad knowledge of PSMA ligands and the demonstrated efficacy of Ac-225-PSMA-617.