DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of invention Group I (claim(s) 31-46 drawn to a liquid formulation comprising recombinant human granulocyte macrophage colony stimulating factor, recombinant human albumin, polyethylene and mannitol) in the reply filed on 3/09/2026 is acknowledged.
3. The election without traverse filed 3/09/2026 is acknowledged. Claims 31-46 are pending and under examination.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted 10/03/2025 and 03/09/2026 and the references cited therein have been considered, unless indicated otherwise.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
5. Claims 31-34, 36-39 and 43-46 are rejected under 35 U.S.C. 103 as being unpatentable over Eriksen, et al. (WO 2020/002650 A1, published 02 January 2020).
The instant claims are drawn to a stable liquid formulation of recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF), recombinant human albumin, polyethylene glycol-4000 and mannitol.
Eriksen, et al. teach a stable liquid formulation of molgramostim (0.15 mg/ml which is converted to 150 µg/ml that meets the limitation of instant claim 31) which is a type of rhGM-CSF, mannitol (50 mg/ml which meets the limitation of instant claim 31 and 32), Magrocol-4000 (19.4 mg/ml) which is also known as polyethylene glycol-4000 and human serum albumin (1 mg/ml which meets the limitation of instant claim 31 and 32) (page 2, paragraph 2). Eriksen, et al. further teach commercial pharmaceutical formulation of human GM-CSF use human serum albumin or recombinant human albumin as a stabilizer (page 3, paragraph 3). Eriksen, et al. further teach the GM-CSF dosage can be .2mg/ml which is converted to 200 µg/ml which meets the limitation of instant claim 32 (page 29, paragraph 3-6). Eriksen, et al. further teach the formulation can contain polyethylene glycol as a stabilizer and the concentration of the stabilizer can be at a dosage of 0.1-5mg/ml which is within the range taught by instant claim 31 and 32 (page 18-19, stabilizer section).
Regarding instant claim 36, Eriksen, et al. teach figure 12 and 65 is a graph showing the minimum purity, by showing the relative GM-CSF areas, throughout all stress conditions determined by RP-HPLC (page 10, figure 12 description and figure 65). This meets the limitation of instant claim 36 as Eriksen, et al. use HPLC to determine impurity as taught in instant claim 36.
Regarding instant claim 37 and 38, Eriksen, et al. teach formulations of embodiments of the present invention may comprise a buffer, such as disodium phosphate (Na2HPO4) (page 2, paragraph 2).
Regarding instant claim 39, Eriksen, et al. teach the polymer or the surfactant is present in an amount of 0.1- 5mg/ml and the surfactant is P80, known as Polysorbate 80, also known as Tween 80 (page 19, 3rd full paragraph).
Regarding instant claim 43, Eriksen, et al. teach the presence of mannitol reduces the amount of shrinkage of the lyo cake, following lyophilization of the formulation. Eriksen, et al. teach the formulation is lyophilized (page 20, 4th full paragraph).
Regarding instant claim 44 and 45, Eriksen, et al. teach the use of the formulations of the present invention is for the treatment of super-orphan lung diseases such as pulmonary alveolar proteinosis. This formula is used for pulmonary treatment which required pulmonary administration. One of ordinary skill in the art would be able to reasonably conclude that the formulation can be used for pulmonary administration that requires administration to the lungs (page 35, 1st full paragraph). Additionally, although the reference teaches instant claim 44 and 45, it is noted that claims 44 and 45 are intended use limitations. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Regarding instant claim 46, Eriksen, et al. teach the formulation can be administered through nasal inhalation (page 36, paragraph 2).
6. Claims 31-39 and 43-46 are rejected under 35 U.S.C. 103 as being unpatentable over Eriksen, et al. (WO 2020/002650 A1, published 02 January 2020) in view of Lee, et al. (U.S. Patent 9,867,777 B2, issued 01/16/2018)
The instant claims are drawn to a stable liquid formulation of recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF), recombinant human albumin, polyethylene glycol-4000 and mannitol. Claim 35 is drawn to the liquid formulation of claim 31, wherein less than 5% of impurity is formed in the liquid formulation after 6 months of storage at 25 °C.
Eriksen, et al. teach a stable liquid formulation of molgramostim (0.15 mg/ml which is converted to 150 µg/ml that meets the limitation of instant claim 31) which is a type of rhGM-CSF, mannitol (50 mg/ml which meets the limitation of instant claim 31 and 32), Magrocol-4000 (19.4 mg/ml) which is also known as polyethylene glycol-4000 and human serum albumin (1 mg/ml which meets the limitation of instant claim 31 and 32) (page 2, paragraph 2). Eriksen, et al. further teach commercial pharmaceutical formulation of human GM-CSF use human serum albumin or recombinant human albumin as a stabilizer (page 3, paragraph 3). Eriksen, et al. further teach the GM-CSF dosage can be .2mg/ml which is converted to 200 µg/ml which meets the limitation of instant claim 32 (page 29, paragraph 3-6). Eriksen, et al. further teach the formulation can contain polyethylene glycol as a stabilizer and the concentration of the stabilizer can be at a dosage of 0.1-5mg/ml which is within the range taught by instant claim 31 and 32 (page 18-19, stabilizer section). Regarding instant claim 36, Eriksen, et al. teach figure 12 and 65 is a graph showing the minimum purity, by showing the relative GM-CSF areas, throughout all stress conditions determined by RP-HPLC (page 10, figure 12 description and figure 65). This meets the limitation of instant claim 36 as Eriksen, et al. use HPLC to determine impurity as taught in instant claim 36. Regarding instant claim 37 and 38, Eriksen, et al. teach formulations of embodiments of the present invention may comprise a buffer, such as disodium phosphate (Na2HPO4) (page 2, paragraph 2). Regarding instant claim 39, Eriksen, et al. teach the polymer or the surfactant is present in an amount of 0.1- 5mg/ml and the surfactant is P80, known as Polysorbate 80, also known as Tween 80 (page 19, 3rd full paragraph). Regarding instant claim 43, Eriksen, et al. teach the presence of mannitol reduces the amount of shrinkage of the lyo cake, following lyophilization of the formulation. Eriksen, et al. teach the formulation is lyophilized (page 20, 4th full paragraph). Regarding instant claim 44 and 45, Eriksen, et al. teach the use of the formulations of the present invention is for the treatment of super-orphan lung diseases such as pulmonary alveolar proteinosis. This formula is used for pulmonary treatment which required pulmonary administration. One of ordinary skill in the art would be able to reasonably conclude that the formulation can be used for pulmonary administration that requires administration to the lungs (page 35, 1st full paragraph). Additionally, although the reference teaches instant claim 44 and 45, it is noted that claims 44 and 45 are intended use limitations. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Eriksen, et al. does not teach less than 5% of impurity is formed in the liquid formulation after 6 months of storage at 25 °C recited in instant claim 35
However, Lee, et al. teach a liquid formulation of G-CSF can retain 95% or higher of the original activity having been stored at 25° C for 6 months (paragraph 33). Lee, et al. further teach proteins such as G-CSF, their storage stability is important in suppressing the potential generation of G-CSF-like antigenic materials as well as guaranteeing accurate administration amounts (paragraph 33). One of ordinary skill in the art could reasonably apply the optimal storage techniques of Lee, et al. to Eriksen, et al., since Lee, et al. states that storage ability stability is important in making sure the protein has less impurity and accurate administrations amount as well as both teach similar liquid formulations. Applying a known technique to a known product ready for improvement to yield predictable results is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, D.).
7. Claims 31-34, 36-39 and 41-46 are rejected under 35 U.S.C. 103 as being unpatentable over Eriksen, et al. (WO 2020/002650 A1, published 02 January 2020) in view of Luisetti, et al. (Luisetti M, Kroneberg P, Suzuki T, Kadija Z, Muellinger B, Campo I, Gleske J, Rodi G, Zimlich WC, Mariani F, Ferrari F, Frey M, Trapnell BC. Physical properties, lung deposition modeling, and bioactivity of recombinant GM-CSF aerosolized with a highly efficient nebulizer. Pulm Pharmacol Ther. 2011 Feb;24(1):123-7. doi: 10.1016/j.pupt.2010.08.004. Epub 2010 Aug 20. PMID: 20728558.)
The instant claims are drawn to a stable liquid formulation of recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF), recombinant human albumin, polyethylene glycol-4000 and mannitol.
Eriksen, et al. teach a stable liquid formulation of molgramostim (0.15 mg/ml which is converted to 150 µg/ml that meets the limitation of instant claim 31) which is a type of rhGM-CSF, mannitol (50 mg/ml which meets the limitation of instant claim 31 and 32), Magrocol-4000 (19.4 mg/ml) which is also known as polyethylene glycol-4000 and human serum albumin (1 mg/ml which meets the limitation of instant claim 31 and 32) (page 2, paragraph 2). Eriksen, et al. further teach commercial pharmaceutical formulation of human GM-CSF use human serum albumin or recombinant human albumin as a stabilizer (page 3, paragraph 3). Eriksen, et al. further teach the GM-CSF dosage can be 0.2 mg/ml which is converted to 200 µg/ml which meets the limitation of instant claim 32 (page 29, paragraph 3-6). Eriksen, et al. further teach the formulation can contain polyethylene glycol as a stabilizer and the concentration of the stabilizer can be at a dosage of 0.1-5mg/ml which is within the range taught by instant claim 31 and 32 (page 18-19, stabilizer section).
Regarding instant claim 36, Eriksen, et al. teach figure 12 and 65 is a graph showing the minimum purity, by showing the relative GM-CSF areas, throughout all stress conditions determined by RP-HPLC (page 10, figure 12 description and figure 65). Regarding instant claim 37 and 38, Eriksen, et al. teach formulations of embodiments of the present invention may comprise a buffer, such as disodium phosphate (Na2HPO4) (page 2, paragraph 2). Regarding instant claim 39, Eriksen, et al. teach the polymer or the surfactant is present in an amount of 0.1- 5mg/ml and the surfactant is P80, known as Polysorbate 80, also known as Tween 80 (page 19, 3rd full paragraph). Regarding instant claim 43, Eriksen, et al. teach the presence of mannitol reduces the amount of shrinkage of the lyo cake, following lyophilization of the formulation. Eriksen, et al. teach the formulation is lyophilized (page 20, 4th full paragraph). Regarding instant claim 44 and 45, Eriksen, et al. teach the use of the formulations of the present invention is for the treatment of super-orphan lung diseases such as pulmonary alveolar proteinosis. This formula is used for pulmonary treatment which required pulmonary administration. One of ordinary skill in the art would be able to reasonably conclude that the formulation can be used for pulmonary administration that requires administration to the lungs (page 35, 1st full paragraph). Additionally, although the reference teaches instant claim 44 and 45, it is noted that claims 44 and 45 are intended use limitations. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Regarding instant claim 46, Eriksen, et al. teach the formulation can be administered through nasal inhalation (page 36, paragraph 2).
Eriksen, et al. do not specifically teach the liquid formulation is nebulized and do not teach the biological potency of the liquid formulation.
However, Luisetti, et al. teach recombinant human GM-CSF (Sargramostim) was lyophilized and dissolved in 1 ml saline. AKITA APIXNEB nebulizer handset was used in all experiments (section 2, methods). Regarding biological activity and potency, Luisetti, et al. further teach the concentration of rhGM-CSF determined by ELISA in the post-aerosolization samples was 94.1%. Luisetti, et al. further teach the use of this nebulizer is to treat pulmonary alveolar proteinosis (PAP). Luisetti, et al. further teach that the use of nebulizer resulted in improvement in 50% of the patients. The nebulizer apparatus taught by Luisetti, et al. is capable of providing optimal delivery of GM-CSF (section 3.3, biological activity).
It would have been prima facie obvious to one of ordinary skill in the art for one ordinary skill in the art could reasonably combine the liquid formulation of Eriksen, et al. and the delivery mechanism taught by Luisetti, et al. as Luisetti, et al. taught this is an optimal delivery system for GM-CSF with patient with PAP. The instant claims 44 and 45 state the liquid formulation taught in instant claim 33 is formulated for pulmonary administration and administration for the lungs. Luisetti, et al. teach that the nebulizer apparatus is an optimal delivery system for GM-CSF with patient PAP, which is involves the pulmonary system and is a lung disease. Eriksen, et al. teach that the liquid formulation can be used through inhalation. Luisetti, et al. provides a method of inhalation through a nebulizer. It would be obvious to one of ordinary skill in the art to use the nebulizer of Luisetti, et al. with the composition of Eriksen, et al. since it was stated that the formulation of Eriksen can be used through inhalation and Luisetti, et al. provides the nebulizer. Applying a known technique to a known product ready for improvement to yield predictable results is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, D.).
8. Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Eriksen, et al. in view of Luisetti, et al. and Lee, et al as applied to claims 31-39 and 41-46 above, and in further view of Hertel (Hertel, S. (2014, May 28). Pulmonary Delivery of Pharmaceutical Proteins by Means of Vibrating Mesh Nebulization. https://edoc.ub.uni-muenchen.de/17279/1/Hertel_Sebastian.pdf)
Instant claim 40 is drawn to the liquid formulation of claim 31, wherein an osmolality of the formulation is from 250 to 375 mOsm/L.
The teachings of Eriksen, et al. and Luisetti, et al. are taught above.
Eriksen, et al. and Luisetti, et al. do not specifically teach the formulation has an osmolality of 250-375 mOsm/L.
However, Hertel teaches protein formulation for purpose of pulmonary delivery involves some special aspects and limitations to consider. Hertel further teaches inhalable protein formulations have to maintain protein stability during production, shelf life and handling. One of those aspects to consider is osmolality. Hertel teaches osmolality in the range of 150-549 mOsm/L was well tolerated (page 131). It would have been prima facie obvious at the time of the invention to incorporate the optimal osmolality taught by Hertel and incorporate it into the liquid formulation taught by Eriksen, et al. and the nebulizer mechanism taught by Luisetti, et al, as Hertel teaches the optimal osmolality for a liquid formulation for the purpose of pulmonary delivery would have an osmolality that encompasses the range taught by instant claim 40. A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
Conclusion
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Syed J Abbas whose telephone number is (571)272-0015. The examiner can normally be reached M-Th, 9:00AM-4:00PM.
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/SYED J ABBAS/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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