Obviousness

The obviousness of US patent 12233106 under 35 U.S.C. § 103 can be assessed by identifying combinations of the cited prior art references that would render the patent's claims obvious to a Person Having Ordinary Skill in the Art (PHOSITA). A PHOSITA in this field would be a scientist or clinician with expertise in peptide therapeutics, endocrinology, skeletal development, and pharmaceutical formulation, likely familiar with the research and development pipeline for rare diseases, particularly those affecting bone growth.

The prior art overwhelmingly consists of patent documents and international applications from the same assignee, Biomarin Pharmaceutical Inc., indicating a continuous research and development effort. This body of prior art establishes the foundation for C-type natriuretic peptide (CNP) variants, their improved pharmacokinetic properties, and their general therapeutic application for skeletal dysplasias.

Motivation to Combine Prior Art References

A PHOSITA would have several motivations to combine the teachings of the prior art:

1. Overcoming Limitations of Wild-Type CNP: Non-patent literature (NPL), such as J. Clin. Endocrinol. Metab., 78: 1428-35 (1994), highlights the critical limitation of wild-type CNP's short half-life in plasma. This provides a strong motivation to utilize or develop CNP variants with increased serum half-life and resistance to degradation, as extensively taught in earlier Biomarin patents (e.g., U.S. Pat. No. 8,198,242; International Application WO 2009/067639).
2. Addressing Skeletal Dysplasias: The NPL (e.g., Olney et al., J. Clin. Endocrinol. Metab. 91(4): 1229-1232 (2006); Bartels et al., Am. J. Hum. Genet. 75: 27-34 (2004)) clearly links CNP signaling to bone growth and associated disorders like dwarfism. Crucially, International Application PCT/US2020/045885 explicitly describes "hydrophobic peptide salts of CNP variants useful to treat skeletal dysplasias." This provides a direct and explicit motivation to apply improved CNP variants to the treatment of skeletal dysplasias.
3. Targeting Pediatric Populations: Skeletal dysplasias are often congenital or manifest in early childhood. The inherent goal of treating these conditions naturally extends to pediatric patients, making it obvious to investigate and optimize treatments for children. Tailoring dosages and treatment regimens for different pediatric age groups is a routine clinical practice.
4. Developing Stable and Effective Formulations: The successful delivery of any peptide therapeutic requires a stable and administrable pharmaceutical formulation. Earlier Biomarin patents (e.g., U.S. Pat. No. 8,198,242) describe general methods for formulating CNP variants. A PHOSITA would routinely select and optimize standard pharmaceutical excipients (buffers, isotonicity agents, stabilizers, anti-adsorbent agents) and adjust parameters like pH to achieve optimal stability, solubility, and injectability for a given peptide.

Obviousness Analysis of US12233106 Claims

1. Method Claims (Claims 1, 9, 17, 25)

• Claim 1 (Treating skeletal dysplasia in 2-5-year-olds): A combination of U.S. Pat. No. 8,198,242 (or any other "Core CNP Variant" patent/application like WO 2009/067639 for improved CNP variants) with PCT/US2020/045885 (explicitly teaching CNP variants for skeletal dysplasias) and general knowledge of pediatric disease management would render this claim obvious. The motivation stems from the need to use stable CNP variants for a known indication (skeletal dysplasia) that presents in childhood. Adjusting the dose for a specific pediatric age range (2-5 years) to achieve an "effective amount" is a routine optimization that would be performed by a PHOSITA during preclinical and clinical development.
• Claim 9 (Treating skeletal dysplasia in subjects <2 years old): The same combination and reasoning as for Claim 1 applies. Extending the treatment to younger pediatric patients (e.g., <2 years old) is a logical progression of treatment strategy for a chronic condition diagnosed early in life. The patent itself in its definitions states the disclosure relates to treatment in "children between 2 and 5 years old, and in particular children less than or about 2 years old." This indicates the age ranges were known targets.
• Claim 17 (Enhancing growth velocity in subjects <2 years old): This claim would be obvious based on the combination of U.S. Pat. No. 8,198,242 (or similar "Core CNP Variant" patents), PCT/US2020/045885, and the NPL (e.g., Olney et al., Bartels et al.) explicitly linking CNP signaling to bone growth and dwarfism. Since skeletal dysplasias are characterized by impaired growth, using CNP variants to "enhance or increase growth velocity" is a direct and expected outcome based on CNP's known mechanism of action. Administering this to a subject less than or about 2 years old, where growth potential is highest, is a logical therapeutic choice. The patent itself notes, "mice engineered to produce elevated levels of CNP display elongated long bones and vertebrae," further reinforcing the expected outcome of increased growth.
• Claim 25 (Enhancing growth velocity in subjects 2-5 years old): The same reasoning as for Claim 17 applies. The extension of the treatment to the 2-5 year old age group is a routine clinical optimization to address the condition across a broader pediatric spectrum.

2. Pharmaceutical Composition Claims (Claims 33, 42, 43, 44)

• Claim 33 (Composition with CNP variant, excipient, pH 4-6): This claim would be obvious from the combination of International Application PCT/US2020/051100 (disclosing specific CNP sequence variants like Pro-Gly-CNP-37) or PCT/US2020/045885 (disclosing hydrophobic peptide salts of CNP variants for skeletal dysplasias), with U.S. Pat. No. 8,198,242 (discussing general formulation principles for CNP variants) and general pharmaceutical knowledge. Choosing a pH range of 4-6 for peptide stability is a well-known strategy in pharmaceutical formulation.
• Claims 42, 43, 44 (Specific liquid formulations with detailed excipient concentrations and pH): These claims recite highly specific formulations. However, a PHOSITA would find these obvious to arrive at through routine experimentation, given the teachings of earlier Biomarin patents (e.g., U.S. Pat. No. 8,198,242, which mentions exemplary CNP peptide formulations) and standard pharmaceutical development practices. The specific excipients listed (citric acid monohydrate/sodium citrate dihydrate as buffers, trehalose dihydrate/D-mannitol as isotonicity agents/bulking agents, L-methionine as stabilizer, polysorbate 80 as anti-adsorbent) are all common, interchangeable, and well-known components in parenteral formulations for peptides. The precise concentrations and pH (e.g., pH 5.5 in Claims 43 and 44) would be optimized through routine stability studies and compatibility tests, not through inventive steps. The differences in CNP variant concentration (2.0 mg/ml in Claim 43 vs. 0.8 mg/ml in Claim 44) represent routine adjustments for dosage flexibility.

3. Kit Claim (Claim 45)

• Claim 45 (Kit with lyophilized formulation and instructions): This claim would be obvious from combining any of the composition claims (e.g., Claim 33 or the underlying teachings of the earlier Biomarin patents/PCTs) with general commercial practices for packaging and distributing pharmaceutical products. Once a stable, lyophilized formulation of a CNP variant is developed (which is a common technique for peptide drugs), preparing a kit with a sterile container, a reconstituting liquid (implied), and instructions for use in treating skeletal dysplasia in children is a routine commercial step, not an inventive one. The instructions for reconstituting to a specific pH range (4-6) are a direct consequence of the optimal formulation parameters.

Conclusion on Obviousness

Considering the cited prior art, particularly the extensive patent family from Biomarin Pharmaceutical Inc., many of the claims of US12233106 would likely be found obvious to a PHOSITA. The core invention of using CNP variants with improved properties to treat skeletal dysplasias was well-established. The specific age ranges for treatment, the quantified improvements in growth velocity, and the precise formulations with standard excipients and optimized concentrations represent routine clinical and pharmaceutical development steps rather than inventive breakthroughs. The motivation to combine the known CNP variants with the known indication in children, and to formulate them effectively, flows directly from the existing technical landscape and the clear problem-solving objectives present in the prior art.